Cinnoline derivatives and use as medicine

ABSTRACT

The invention relates to the use of cinnoline derivatives of formula (I) 
                         
wherein Z represents —O—, —NH—, —S— or —CH 2 —; m is an integer from 1 to 5; R 1  represents hydrogen, hydroxy, halogeno, nitro, cyano, trifluoromethyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or NR 6 R 7  (wherein R 6  and R 7 , which may be the same or different, each represents hydrogen or C 1-3 alkyl); R 2  represents hydrogen, hydroxy, fluoro, chloro, methoxy, amino or nitro; R 3  represents hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R 4  represents hydrogen, hydroxy, halogeno, cyano, nitro, amino, trifluoromethyl, C 1-3 alkyl or a group R 5 —X 1  (wherein X 1  represents —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NR 8 CO—, —CONR 9− , —SO 2 NR 10 —, —NR 11 SO 2 — or —NR 12 — (wherein R 8 , R 9 , R 10 , R 11  and R 12  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl) and R 5 is an optionally substituted alkyl, carbocylic or heterocylic group which may be saturated or unsaturated and may be directly linked to the cinnoline ring or be linked via a carbon chain which may have heteroatom linking groups within it and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being, processes for the preparation of such derivatives, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

This is a Continuation of application Ser. No. 09/142,839, filed Apr.13, 1999, now U.S. Pat. No. 6,514,971 which is the national stageapplication of PCT/GB97/00650 filed Mar. 11, 1997.

Each listed U.S. Patents and/or application is entirely incorporatedherein by reference in its entirety.

The present invention relates to the use of cinnoline derivatives in themanufacture of medicaments for use in the production of antiangiogenicand/or vascular permeability reducing effects in warm-blooded animalssuch as humans, to a method for the treatment of disease statesassociated with angiogenesis and/or increased vascular permeability, tocertain such cinnoline derivatives for use in medicine and to certaincinnoline derivatives per se, processes for their preparation andpharmaceutical compositions containing them as active ingredient.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57–66; Folkman,1995, Nature Medicine 1: 27–31). Alteration of vascular permeability isthought to play a role in both normal and pathological physiologicalprocesses (Cullinan-Bove et al, 1993, Endocrinology 133: 829–837; Sengeret al, 1993, Cancer and Metastasis Reviews, 12: 303–324). Severalpolypeptides with in vitro endothelial cell growth promoting activityhave been identified including, acidic and basic fibroblast growthfactors (aFGF & bFGF) and vascular endothelial growth factor (VEGF). Byvirtue of the restricted expression of its receptors, the growth factoractivity of VEGF, in contrast to that of the FGFs, is relativelyspecific towards endothelial cells. Recent evidence indicates that VEGFis an important stimulator of both normal and pathological angiogenesis(Jakeman et al, 1993, Endocrinology, 133: 848–859; Kolch et al, 1995,Breast Cancer Research and Treatment, 36:139–155) and vascularpermeability (Connolly et al, 1989, J. Biol. Chem. 264: 20017–20024).Antagonism of VEGF action by sequestration of VEGF with antibody canresult in inhibition of tumour growth (Kim et al, 1993, Nature 362:841–844).

Receptor tyrosine kinases (RTKs) are important in the transmission ofbiochemical signals across the plasma membrane of cells. Thesetransmembrane molecules characteristically consist of an extracellularligand-binding domain connected through a segment in the plasma membraneto an intracellular tyrosine kinase domain. Binding of ligand to thereceptor results in stimulation of the receptor-associated tyrosinekinase activity which leads to phosphorylation of tyrosine residues onboth the receptor and other intracellular molecules. These changes intyrosine phosphorylation initiate a signalling cascade leading to avariety of cellular responses. To date, at least nineteen distinct RTKsubfamilies, defined by amino acid sequence homology, have beenidentified. One of these subfamilies is presently comprised by thefms-like tyrosine kinase receptor, Flt or Flt1, the kinase insertdomain-containing receptor, KDR (also referred to as Flk-1), and anotherfms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fltand KDR, have been shown to bind VEGF with high affinity (De Vries etal, 1992, Science 255: 989–991; Terman et al, 1992, Biochem. Biophys.Res. Comm. 1992, 187: 1579–1586). Binding of VEGF to these receptorsexpressed in heterologous cells has been associated with changes in thetyrosine phosphorylation status of cellular proteins and calcium fluxes.

European Patent Publication No. 0326330 discloses certain quinoline,quinazoline and cinnoline plant fungicides. Certain of these plantfungicides are also stated to possess insecticidal and miticidalactivity. There is however no disclosure or any suggestion that any ofthe compounds disclosed may be used for any purpose in animals such ashumans. In particular, the European Patent Publication contains noteaching whatsoever concerning angiogenesis and/or increased vascularpermeability mediated by growth factors such as VEGF.

A number of further documents described hereinafter disclose certaincinnoline derivatives, but none of these documents contain any teachingwhatsoever concerning angiogenesis and/or increased vascular permeabiltymediated by growth factors such as VEGF. Thus J. Med Chem. (1995),38(18), 3482–7 discloses 4-(3-bromoanilino)cinnoline, J. Chem. Soc. C(1968), (9), 1152–5 discloses 6-chloro-4-phenoxycinnoline, J. KarnatakUniv., Sci. (1984), 29, 82–6 discloses certain 4-anilinocinnolines andIndian J. Chem. (1973), 11(3), 211–13 discloses certain4-phenylthiocinnolines. All of these disclosed compounds were tested forphysiological activity, but all except the two specifically namedcompounds below were found to be inactive in the tests employed. J.Karnatak Univ., (1973), 18, 25–30 discloses certain 4-phenoxycinnolinessome of which showed a little antimicrobial activity but none of whichshowed analgesic or antihistaminic activity. J. Karnatak Univ., Sci.(1984), 29, 82–6 discloses two compounds:4-(4-methoxyanilino)-6,7-dimethoxycinnoline and4-(3-chloroanilino)-6,7-dimethoxycinnoline which were tested and werefound to have some anti-inflammatory and antiarthritic activity. Thepapers and patents listed below describe the synthesis of certaincinnolines with a phenyl ring linked via a group selected from —O—, —S—,—NH— and —CH₂— at the 4-position: U.S. Pat. Nos. 5,017,579, 4,957,925,4,994,474, EP 0302793 A2, Arch Pharm (Weinheim) (1970), 303(7), 560–2,J. Med. Chem. (1968), 11, 1270, Indian J. Chem. (1968), 6(7), 350–2, J.Chem. Soc. C (1968), (9), 1156–8, Yakugaku Zasshi (1968), 88(1), 94–7,J. Org. Chem. (1960), 25, 570, J. Org. Chem. (1952), 17, 1571–5, J. Org.Chem. (1953), 18, 1706–8, J. Org. Chem. (1954), 19, 1117–23 and J. Am.Pharm. Assoc. (1959), 48, 135–9, but none of these papers and patentsdisclose any utility at all for the cinnolines they describe.

The present invention is based on the discovery of compounds thatsurprisingly inhibit the effects of VEGF, a property of value in thetreatment of disease states associated with angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation.Compounds of the present invention possess good activity against VEGFreceptor tyrosine kinase whilst possessing some activity againstepidermal growth factor (EGF) receptor tyrosine kinase. Furthermore,compounds of the present invention, possess substantially higher potencyagainst VEGF receptor tyrosine kinase than against EGF receptor tyrosinekinase or FGF R1 receptor tyrosine kinase. Thus compounds of theinvention which have been tested possess activity against VEGF receptortyrosine kinase such that they may be used in an amount sufficient toinhibit VEGF receptor tyrosine kinase whilst demonstrating nosignificant activity against EGF receptor tyrosine kinase or FGF R1receptor tyrosine kinase.

According to one aspect of the present invention there is provided theuse of a compound of the formula I:

[wherein:

-   Z represents —O—, —NH—, —S— or —CH₂—;-   m is an integer from 1 to 5;-   R¹ represents hydrogen, hydroxy, halogeno, nitro, cyano,    trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio or NR⁶R⁷    (wherein R⁶ and R⁷, which may be the same or different, each    represents hydrogen or C₁₋₃alkyl);-   R² represents hydrogen, hydroxy, fluoro, chloro, methoxy, amino or    nitro;-   R³ represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,    C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino or nitro;-   R⁴ represents hydrogen, hydroxy, halogeno, cyano, nitro, amino,    trifluoromethyl, C₁₋₃alkyl or a group R⁵—X¹ (wherein X¹ represents    —O—, —CH₂—, —S—, —SO—, —SO₂—, —NR⁸CO—, —CONR⁹—, —SO₂NR¹⁰—, —NR¹¹SO₂—    or —NR¹²— (wherein R⁸, R⁹, R¹⁰, R¹¹ and R¹² each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁵ is    selected from one of the following fourteen groups:-   1) C₁₋₅alkyl, C₁₋₅hydroxyalkyl, C₁₋₅fluoroalkyl, C₁₋₅aminoalkyl;-   2) C₁₋₅alkylX²COR¹³ (wherein X² represents —O— or NR¹⁴ (in which R¹⁴    represents hydrogen, C₁₋₃alkyl or C₃alkoxyC₂₋₃alkyl) and R¹³    represents C₁₋₃alkyl, NR¹⁵R¹⁶ or OR¹⁷ (wherein R¹⁵, R¹⁶ and R¹⁷    which may be the same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl), with the proviso that when X² is —O—, R¹³ is    not OR¹⁷);-   3) C₁₋₅alkylX³R¹⁸ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,    —OCO—, —NR¹⁹CO—, —CONR²⁰—, —SO₂NR²¹—, —NR²²SO₂— or —NR²³— (wherein    R¹⁹, R²⁰, R²¹, R²² and R²³ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁸ represents hydrogen,    C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which C₁₋₃alkyl group may bear one or    two substituents selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy    and which cyclic group may bear one or two substituents selected    from oxo, hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and    C₁₋₄alkoxy);-   4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²⁴ (wherein X⁴ and X⁵ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR²⁵CO—,    —CONR²⁶—, —SO₂NR²⁷—, —NR²⁸SO₂— or —NR²⁹— (wherein R²⁵, R²⁶, R²⁷, R²⁸    and R²⁹ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²⁴ represents hydrogen or C₁₋₃alkyl);-   5) C₁₋₅alkylR³⁰ (wherein R³⁰ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear one    or two substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);-   6) C₂₋₅alkenylR³⁰ (wherein R³⁰ is as defined hereinbefore);-   7) C₂₋₅alkynylR³⁰ (wherein R³⁰ is as defined hereinbefore);-   8) (CH₂)_(n)R³¹ (wherein n is an integer from 0 to 5 and R³¹ is a    phenyl group, a pyridone group or a 5 or 6 membered aromatic    heterocyclic group with 1 to 3 heteroatoms selected from O, N and S,    which phenyl, pyridone or aromatic heterocyclic group may carry up    to 5 substituents selected from hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, carboxy, cyano,    CONR³²R³³ and NR³⁴COR³⁵ (wherein R³², R³³, R³⁴ and R³⁵, which may be    the same or different, each represents hydrogen, C₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   9) C₂₋₅alkenylR³¹ (wherein R³¹ is as defined hereinbefore);-   10) C₂₋₅alkynylR³¹ (wherein R³¹ is as defined hereinbefore);-   11) C₁₋₅alkylX⁶R³¹ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁶CO—, —CONR³⁷—, —SO₂NR³⁸—, —NR³⁹SO₂— or —NR⁴⁰— (wherein R³⁶,    R³⁷, R³⁸, R³⁹ and R⁴⁰ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³¹ is as defined    hereinbefore);-   12) C₂₋₅alkenylX⁷R³¹ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴¹CO—, —CONR⁴²—, —SO₂NR⁴³—, —NR⁴⁴SO₂— or —NR⁴⁵— (wherein R⁴¹,    R⁴², R⁴³, R⁴⁴ and R⁴⁵ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³¹ is as defined    hereinbefore);-   13) C₂₋₅alkynylX⁸R³¹ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴⁶CO—, —CONR⁴⁷—, —SO₂NR⁴⁸—, —NR⁴⁹SO₂— or —NR⁵⁰— (wherein R⁴⁶,    R⁴⁷, R⁴⁸, R⁴⁹ and R⁵⁰ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³¹ is as defined    hereinbefore);-   14) C₁₋₃alkylX⁹C₁₋₃alkylR³¹ (wherein X⁹ represents —O—, —S—, —SO—,    —SO₂—, —NR⁵¹CO—, —CONR⁵²—, —SO₂NR⁵³—, —NR⁵⁴SO₂— or —NR⁵⁵— (wherein    R⁵¹, R⁵², R⁵³, R⁵⁴ and R⁵⁵ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³¹ is as defined    hereinbefore))];    and salts thereof, in the manufacture of a medicament for use in the    production of an antiangiogenic and/or vascular permeability    reducing effect in a warm-blooded animal such as a human being.

According to a further aspect of the present invention there is provideda method for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula I, as defined hereinbefore, or a pharmaceutically acceptablesalt thereof.

-   Z is advantageously —S—, preferably —O—, but especially —NH—.-   m is advantageously an integer from 2 to 5, preferably 2 or 3,    especially 3.-   R¹ is advantageously hydrogen, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,    amino, cyano, nitro or trifluoromethyl.-   R¹ is preferably hydrogen, hydroxy, methyl, ethyl, methoxy or    ethoxy, more preferably hydrogen, hydroxy, methyl or methoxy but    especially methoxy.-   R² is advantageously hydrogen, hydroxy, fluoro, methoxy, amino or    nitro.-   R² is preferably hydrogen, amino or nitro, but especially hydrogen.

In one embodiment of the present invention R³ represents hydroxy,halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, trifluoromethyl, cyano, amino or nitro.

Advantageously in another embodiment of the present invention one R³substituent is meta-hydroxy and the other one or more are each selectedfrom halogeno, methyl and methoxy.

In another embodiment of the invention the phenyl group bearing (R³)_(m)is preferably of the formula II:

wherein:

-   R^(a) represents hydrogen, methyl, fluoro or chloro, preferably    hydrogen, fluoro or chloro, especially fluoro;-   R^(b) represents hydrogen, methyl, methoxy, bromo, fluoro or chloro;-   R^(c) represents hydrogen or hydroxy, especially hydroxy;-   R^(d) represents hydrogen, fluoro or chloro, more preferably    hydrogen or fluoro, especially fluoro.

Preferably in another embodiment of the invention two R³ substituentsare halogeno, especially ortho, ortho′-difluoro, and the other one ormore are each selected from halogeno, hydroxy and methyl, morepreferably from halogeno and methyl.

More preferably in another embodiment of the invention the phenyl groupbearing (R³)_(m) carries at least two substituents of which one isfluoro, especially ortho-fluoro.

In a particular aspect of the present invention, the phenyl groupbearing (R³)_(m) is the 2-fluoro-5-hydroxy-4-methylphenyl group, the4-chloro-2-fluoro-5-hydroxyphenyl group, the 4-bromo-2,6-difluorophenylgroup, the 4-chloro-2,6-difluorophenyl group, the4-chloro-2-fluorophenyl group, the 4-chloro-3-hydroxyphenyl group, the4-bromo-3-hydroxyphenyl group, the 3-hydroxy-4-methyl group or the4-bromo-2-fluoro-5-hydroxyphenyl group.

In a particularly preferred aspect of the invention the phenyl groupbearing (R³)_(m) is the 2-fluoro-5-hydroxy-4-methylphenyl group, the4-chloro-2-fluoro-5-hydroxyphenyl group, the 4-chloro-3-hydroxyphenylgroup, the 4-bromo-3-hydroxyphenyl group, the 3-hydroxy-4-methyl groupor the 4-bromo-2-fluoro-5-hydroxyphenyl group.

Conveniently X¹ represents —O—, —S—, —CH₂—, —NR⁸CO—, —CONR⁹—, —NR¹¹SO₂—or —NR¹²— (wherein R⁸, R⁹, R¹¹ and R¹² each independently representshydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Advantageously X¹ represents —O—, —S—, —NR⁸CO—, —NR¹¹SO₂— or —NR¹²—(wherein R⁸, R¹¹ and R¹² each independently represents hydrogen,C₁₋₂alkyl or C₁₋₂alkoxyethyl).

Preferably X¹ represents —O—, —S—, —NR⁸CO— (wherein R⁸ representshydrogen or methyl) or NH.

More preferably X¹ represents —O— or —NHCO—, especially —O—.

-   Advantageously X² represents —O— or —NR¹⁴— (wherein R¹⁴ represents    hydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).    Advantageously X³ represents —O—, —S—, —SO—, —SO₂—, —NR¹⁹CO—,    —NR²²SO₂— or —NR²³— (wherein R¹⁹, R²² and R²³ each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).    Preferably X³ represents —O—, —S—, —SO—, —SO₂— or —NR²³— (wherein    R²³ represents hydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).    More preferably X³ represents —O—, —S—, —SO—, —SO₂— or —NR²³—    (wherein R²³ represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl),    especially —O— or —NR²³— (wherein R²³ represents hydrogen or    C₁₋₂alkyl).    Advantageously X⁴ and X⁵ which may be the same or different each    represents —O—, —S—, —SO—, —SO₂— or —NR²⁹— (wherein R²⁹ represents    hydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl).    Preferably X⁴ and X⁵ which may be the same or different each    represents —O—, —S— or —NR²⁹— (wherein R²⁹ represents hydrogen,    C₁₋₃alkyl or C₁₋₂alkoxyethyl).    More preferably X⁴ and X⁵ which may be the same or different each    represents —O—, —S— or —NR²⁹— (wherein R²⁹ represents hydrogen or    C₁₋₃alkyl), especially —O— or —NH—.    Advantageously X⁶ represents —O—, —S— or —NR⁴⁰— (wherein R⁴⁰    represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).    Preferably X⁶ represents —O— or —NR⁴⁰— (wherein R⁴⁰ represents    hydrogen or C₁₋₂alkyl).    Advantageously X⁷ represents —O—, —S— or —NR⁴⁵— (wherein R⁴⁵    represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).    Preferably X⁷ represents —O— or —NR⁴⁵— (wherein R⁴⁵ represents    hydrogen or C₁₋₂alkyl).    Advantageously X⁸ represents —O—, —S— or —NR⁵⁰— (wherein R⁵⁰    represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).    Preferably X⁸ represents —O— or —NR⁵⁰— (wherein R⁵⁰ represents    hydrogen or C₁₋₂alkyl).    Advantageously X⁹ represents —O—, —S— or —NR⁵⁵— (wherein R⁵⁵    represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl).    Preferably X⁹ represents —O— or —NR⁵⁵— (wherein R⁵⁵ represents    hydrogen or C₁₋₂alkyl).

Conveniently R⁴ is hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl,cyano, amino or a group R⁵—X¹ (wherein X¹ is as defined hereinbefore andR⁵ is selected from one of the following fourteen groups:

-   1) C₁₋₅alkyl, C₂₋₅hydroxyalkyl, C₁₋₅fluoroalkyl, C₂₋₅aminoalkyl;-   2) C₂₋₃alkylX²COR¹³ (wherein X² is as defined hereinbefore and R¹³    represents C₁₋₃alkyl, NR¹⁵R¹⁶ or OR¹⁷ (wherein R¹⁵, R¹⁶ and R¹⁷    which may be the same or different are each C₁₋₂alkyl or    C₁₋₂alkoxyethyl) with the proviso that when X² is —O—, R¹³ is not    OR¹⁷);-   3) C₂₋₄alkylX³R¹⁸ (wherein X³ is as defined hereinbefore and R¹⁸    represents hydrogen, C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5 or 6    membered saturated heterocyclic group with one or two heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear one or two substituents selected from oxo, hydroxy, halogeno    and C₁₋₃alkoxy and which cyclic group may bear one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₃alkyl,    C₁₋₃hydroxyalkyl and C₁₋₃alkoxy);-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²⁴ (wherein X⁴ and X⁵ are as defined    hereinbefore and R²⁴ represents hydrogen or C₁₋₃alkyl);-   5) C₁₋₅alkylR⁵⁶ (wherein R⁵⁶ is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    C₁₋₅alkyl through a carbon atom and which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy) or C₂₋₅alkylR⁵⁷ (wherein    R⁵⁷ is a 5 or 6 membered saturated heterocyclic group with one or    two heteroatoms of which one is N and the other is selected    independently from O, S and N, which heterocyclic group is linked to    C₂₋₅alkyl through a nitrogen atom and which heterocyclic group may    bear one or two substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);-   6) C₃₋₄alkenylR⁵⁸ (wherein R⁵⁸ represents R⁵⁶ or R⁵⁷ as defined    hereinbefore);-   7) C₃₋₄alkynylR⁵⁸ (wherein R⁵⁸ represents R⁵⁶ or R⁵⁷ as defined    hereinbefore);-   8) (CH₂)_(n)R³¹ (wherein n is an integer from 0 to 4 and R³¹ is a    phenyl group, a pyridone group or a 5 or 6 membered aromatic    heterocyclic group with 1 to 3 heteroatoms selected from O, N and S,    which phenyl, pyridone or aromatic heterocyclic group may be    substituted as hereinbefore defined, advantageously substituted with    up to 2 substituents as hereinbefore defined, more preferably    substituted with one substituent selected from the group of    substituents as hereinbefore defined);-   9) 1-R³¹prop-1-en-3-yl or 1-R³¹but-2-en-4-yl (wherein R³¹ is as    defined hereinbefore);-   10) 1-R³¹prop-1-yn-3-yl or 1-R³¹but-2-yn-4-yl (wherein R³¹ is as    defined hereinbefore);-   11) C₁₋₅alkylX⁶R³¹ (wherein X⁶ and R³¹ are as defined hereinbefore);-   12) 1-(R³¹X⁷)but-2-en-4-yl (wherein X⁷ and R³¹ are as defined    hereinbefore);-   13) 1-(R³¹X⁸)but-2-yn-4-yl (wherein X⁸ and R³¹ are as defined    hereinbefore);-   14) C₂₋₃alkylX⁹C₁₋₂alkylR³¹ (wherein X⁹ and R³¹ are as defined    hereinbefore)).

Advantageously R⁴ is hydroxy, halogeno, nitro, trifluoromethyl,C₁₋₃alkyl, cyano, amino or a group R⁵—X¹ (wherein X¹ is as definedhereinbefore and R⁵ is selected from one of the following fourteengroups:

-   1) C₁₋₄alkyl, C₂₋₄hydroxyalkyl, C₁₋₄fluoroalkyl, C₂₋₄aminoalkyl;-   2) C₂₋₃alkylX²COR¹³ (wherein X² is as defined hereinbefore and R¹³    represents C₁₋₃alkyl, NR¹⁵R¹⁶ or OR¹⁷ (wherein R¹⁵, R¹⁶ and R¹⁷    which may be the same or different are each C₁₋₂alkyl or    C₁₋₂alkoxyethyl) with the proviso that when X² is —O—, R¹³ is not    OR¹⁷);-   3) C₂₋₄alkylX³R¹⁸ (wherein X³ is as defined hereinbefore and R¹⁸    represents C₁₋₃alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl and    piperidinyl which group is linked to X³ through a carbon atom and    which C₁₋₃alkyl group may bear one or two substituents selected from    oxo, hydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl,    cyclohexyl, pyrrolidinyl or piperidinyl group may carry one    substituent selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy);-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²⁴ (wherein X⁴ and X⁵ are as defined    hereinbefore and R²⁴ represents hydrogen or C₁₋₃alkyl);-   5) C₁₋₄alkylR⁵⁹ (wherein R⁵⁹ is a group selected from pyrrolidinyl,    piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to    C₁₋₄alkyl through a carbon atom and which group may carry one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy) or C₂₋₄alkylR⁶⁰ (wherein R⁶⁰ is a    group selected from morpholino, thiomorpholino, pyrrolidin-1-yl,    piperazin-1-yl and piperidino which group may carry one or two    substituents selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy);-   6) C₃₋₄alkenylR⁶¹ (wherein R⁶¹ represents R⁵⁹ or R⁶⁰ as defined    hereinbefore);-   7) C₃₋₄alkynylR⁶¹ (wherein R⁶¹ represents R⁵⁹ or R⁶⁰ as defined    hereinbefore);-   8) (CH₂)_(n)R³¹ (wherein n is an integer from 1 to 3 and R³¹ is a    pyridone group or a 5 or 6 membered aromatic heterocyclic group with    1 to 2 heteroatoms selected from O, N and S, of which preferably one    is N which pyridone or aromatic heterocyclic group may be    substituted as hereinbefore defined, preferably substituted with one    substituent selected from halogeno, C₁₋₂alkyl, C₁₋₂alkoxy,    C₁₋₂hydroxyalkyl, C₁₋₂hydroxyalkoxy, carboxy, cyano, CONR³²R³³ and    NR³⁴COR³⁵ (wherein R³², R³³, R³⁴ and R³⁵, which may be the same or    different, each represents hydrogen, C₁₋₂alkyl or C₁₋₂alkoxyethyl));-   9) 1-R³¹but-2-en4-yl (wherein R³¹ is as defined hereinbefore);-   10) 1-R³¹but-2-yn-4-yl (wherein R³¹ is as defined hereinbefore);-   11) C₁₋₅alkylX⁶R³¹ (wherein X⁶ and R³¹ are as defined hereinbefore);-   12) 1-(R³¹X⁷)but-2-en-4-yl (wherein X⁷ and R³¹ are as defined    hereinbefore);-   13) 1-(R³¹X⁸)but-2-yn-4-yl (wherein X⁸ and R³¹ are as defined    hereinbefore);-   14) C₂₋₃alkylX⁹C₁₋₂alkylR³¹ (wherein X⁹ and R³¹ are as defined    hereinbefore)).

Preferably R⁴ is hydroxy, halogeno, nitro, trifluoromethyl, C₁₋₃alkyl,cyano, amino or a group R⁵—X¹ (wherein X¹ is as defined hereinbefore andR⁵ is selected from one of the following eight groups:

-   1) C₁₋₃alkyl, C₂₋₃hydroxyalkyl, C₁₋₃fluoroalkyl, C₂₋₃aminoalkyl;-   2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl;-   3) C₂₋₃alkylX³R¹⁸ (wherein X³ is as defined hereinbefore and R¹⁸    represents C₁₋₂alkyl, cyclopentyl, cyclohexyl, pyrrolidinyl or    piperidinyl which group is linked to X³ through a carbon atom and    which C₁₋₂alkyl group may bear one or two substituents selected from    hydroxy, halogeno and C₁₋₂alkoxy and which cyclopentyl, cyclohexyl,    pyrrolidinyl or piperidinyl group may carry one substituent selected    from oxo, hydroxy, halogeno, C₁₋₂alkyl, C₁₋₂hydroxyalkyl and    C₁₋₂alkoxy);-   4) C₂₋₃alkylX⁴C₂₋₃alkylX⁵R²⁴ (wherein X⁴ and X⁵ are as defined    hereinbefore and R²⁴ represents hydrogen or C₁₋₂alkyl);-   5) C₁₋₂alkylR⁶² (wherein R⁶² is a group selected from pyrrolidinyl,    piperazinyl, piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl and 1,3-dithian-2-yl, which group is linked to    C₁₋₂alkyl through a carbon atom and which group may carry one    substituent selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy) or C₂₋₃alkylR⁶³ (wherein R⁶³ is a    group selected from morpholino, thiomorpholino, piperidino,    piperazin-1-yl and pyrrolidin-1-yl which group may carry one    substituent selected from oxo, hydroxy, halogeno, C₁₋₂alkyl,    C₁₋₂hydroxyalkyl and C₁₋₂alkoxy);-   6) (CH₂)_(n)R³¹ (wherein n is an integer from 1 to 3 and R³¹ is    selected from a pyridone, pyridyl, imidazolyl, thiazolyl, thienyl,    pyridazinyl and triazolyl group preferably from a pyridone, pyridyl,    imidazolyl, thiazolyl and triazolyl group, more preferably from a    pyridone, pyridyl, imidazolyl and triazolyl group and R³¹ may be    substituted with one substituent selected from halogeno C₁₋₂alkyl,    C₁₋₂alkoxy, C₁₋₂hydroxyalkyl, C₁₋₂hydroxyalkoxy, carboxy, cyano,    CONR³²R³³ and NR³⁴COR³⁵ (wherein R³², R³³, R³⁴ and R³⁵, which may be    the same or different, each represents hydrogen, C₁₋₂alkyl or    C₁₋₃alkoxyC₂₋₃alkyl), more preferably substituted with one    substituent selected from halogeno, C₁₋₂alkyl, C₁₋₂alkoxy and cyano,    especially substituted with one substituent selected from halogeno,    C₁₋₂alkyl and cyano, more especially substituted with one    substituent selected from chloro, fluoro, methyl and ethyl);-   7) C₁₋₅alkylX⁶R³¹ (wherein X⁶ and R³¹ are as defined hereinbefore);-   8) ethylX⁹methylR³¹ (wherein X⁹ and R³¹ are as defined    hereinbefore)).

More preferably R⁴ represents hydroxy, C₁₋₃alkyl, amino, or a groupR⁵—X¹ (wherein X¹ is as defined hereinbefore and R⁵ is methyl, ethyl,trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,3-piperidinopropyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,(1,3-dioxolan-2-yl)methyl, 2-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-(2-hydroxyethylamino)ethyl,3-(2-methoxyethylamino)propyl, 3-(2-hydroxyethylamino)propyl,2-methylthiazol-4-ylmethyl, 2-acetamidothiazol-4-ylmethyl,1-methylimidazol-2-ylmethyl, 2-(imidazol-1-yl)ethyl,2-(1,2,3-triazol-1-yl)ethyl, 2-(1,2,3-triazol-2-yl)ethyl,2-(1,2,4-triazol-1-yl)ethyl, 2-(1,2,4-triazol-4-yl)ethyl,4-pyridylmethyl, 2-(4-pyridyl)ethyl, 3-(4-pyridyl)propyl,2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl or 2-thiomorpholinoethyl,3-thiomorpholinopropyl, 2-(2-methoxyethoxy)ethyl,2-(4-methylpiperazin-1-yl)ethyl or 3-(4-methylpiperazin-1-yl)propyl).

According to another aspect of the present invention there is provided acompound of the formula I as defined hereinbefore with the proviso thatwhere m is 1, R³ is meta-hydroxy and with the further proviso that thecompound of formula I is not4-(2,6-dimethylphenoxy)-6,7-dimethoxycinnoline; and salts thereof, foruse as a medicament.

As indicated above for a compound of formula I, as defined hereinbefore,and salts thereof, for use as a medicament:

-   m is advantageously an integer from 2 to 5, preferably 2 or 3,    especially 3;-   Z is preferably —NH—; and preferably R⁴ represents hydroxy,    C₁₋₃alkyl, amino, or a group R⁵—X¹ (wherein X¹ is as defined    hereinbefore and R⁵ is methyl, ethyl, trifluoromethyl,    2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,    2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,    2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,    2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,    2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,    2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,    3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,    3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,    3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,    2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,    2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,    3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,    2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,    2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl,    2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,    2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,    3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,    2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl or 2-thiomorpholinoethyl,    3-thiomorpholinopropyl, 2-(2-methoxyethoxy)ethyl,    2-(4-methylpiperazin-1-yl)ethyl or    3-(4-methylpiperazin-1-yl)propyl).

According to a further aspect of the present invention there is provideda compound of the formula I as defined hereinbefore with the provisothat where m is 1, R³ is meta-hydroxy and with the further proviso thatthe phenyl group bearing (R³)_(m) is not 3,4-dimethylphenyl and thatwhen the phenyl group bearing (R³)_(m) is 2,5-dichlorophenyl,3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,2-bromo-4-chlorophenyl, 4-bromo-2-chlorophenyl, 2-bromo-4-methylphenyl,2-chloro-4-methylphenyl, 2-chloro-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl,2,5-dichloro-4-hydroxyphenyl or 5-chloro-2-methylphenyl, Z is —NH—; andsalts thereof.

According to a further aspect of the present invention there is provideda compound of the formula I as defined hereinbefore with the provisothat where m is 1, R³ is meta-hydroxy and with the further proviso thatthe phenyl group bearing (R³)_(m) is not 3,4-dimethylphenyl and thatwhen the phenyl group bearing (R³)_(m) is 2,5-dichlorophenyl,3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,3,4-dimethoxyphenyl, 2-bromo-4-chlorophenyl, 4-bromo-2-chlorophenyl,2-bromo-4-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,3,5-dichloro-4-hydroxyphenyl, 2,5-dichloro-4-hydroxyphenyl or5-chloro-2-methylphenyl, Z is —NH—; and salts thereof.

As indicated above for a compound of formula I, as defined hereinbefore,and salts thereof:

-   m is advantageously an integer from 2 to 5, preferably 2 or 3,    especially 3;-   Z is preferably —NH—; and-   preferably R⁴ represents hydroxy, C₁₋₃alkyl, amino, or a group R⁵—X¹    (wherein X¹ is as defined hereinbefore and R⁵ is methyl, ethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl,    3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl,    2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,    2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,    2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,    3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,    2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,    3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,    3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,    2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,    2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,    3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,    2-acetamidothiazol-4-ylmethyl, 1-methylimidazol-2-ylmethyl,    2-(imidazol-1-yl)ethyl, 2-(1,2,3-triazol-1-yl)ethyl,    2-(1,2,3-triazol-2-yl)ethyl, 2-(1,2,4-triazol-1-yl)ethyl,    2-(1,2,4-triazol-4-yl)ethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl,    3-(4-pyridyl)propyl, 2-(4-pyridyloxy)ethyl, 2-(4-pyridylamino)ethyl,    2-(4-oxo-1,4-dihydro-1-pyridyl)ethyl or 2-thiomorpholinoethyl,    3-thiomorpholinopropyl, 2-(2-methoxyethoxy)ethyl,    2-(4-methylpiperazin-1-yl)ethyl or    3-(4-methylpiperazin-1-yl)propyl).

In a particular embodiment of the present invention there is providedthe use of a compound of the formula Ia:

[(wherein:

-   Z^(a) represents —O—, —NH—, —S— or —CH₂—;-   ma is an integer from 1 to 5;-   R^(1a) represents hydrogen, hydroxy, halogeno, C₁₋₃alkyl,    C₁₋₃alkoxy, C₁₋₃alkylthio or NR^(5a)R^(6a) (wherein R^(5a) and    R^(6a), which may be the same or different, each represents hydrogen    or C₁₋₃ alkyl);-   R^(2a) represents hydrogen, hydroxy, fluoro, methoxy, amino or    nitro;-   R^(3a) represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,    C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino or nitro;-   X^(1a) represents —O—, —CH₂—, —S— or NR^(7a) (wherein R^(7a)    represents hydrogen or C₁₋₃ alkyl);-   R^(4a) is selected from the following:-   1) C₁₋₅alkyl, C₁₋₅hydroxyalkyl, C₁₋₅fluoroalkyl, C₁₋₅aminoalkyl;-   2) C₁₋₅alkylX^(2a)COR^(9a) (wherein X^(2a) represents —O— or NR^(8a)    (in which R^(8a) represents hydrogen, C₁₋₃alkyl or C₁₋₃    alkoxyC₂₋₃alkyl) and R^(9a) represents NR^(10a)R^(11a) or OR^(12a)    (wherein R^(10a), R^(11a) and R^(12a) which may be the same or    different are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) with    the proviso that when X^(2a) is —O—, R^(9a) is not OR^(12a));-   3) C₁₋₅alkylX^(3a)R^(14a) (wherein X^(3a) represents —O—, —S—, —SO—,    —SO₂— or NR^(13a) (wherein R^(13a) is hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R^(14a) represents C₁₋₃alkyl, cyclopentyl    or cyclohexyl);-   4) C₁₋₅alkylX^(4a)C₁₋₅alkylX^(5a)R^(15a) (wherein X^(4a) and X^(5a)    which may be the same or different are each —O—, —S—, or NR^(16a)    (wherein R^(16a) is hydrogen or C₁₋₃alkyl) and R^(15a) represents    hydrogen or C₁₋₃alkyl);-   5) C₁₋₅alkylsulphonylNR^(17a)R^(18a) (wherein R^(17a) and R^(18a)    which may be the same or different are each hydrogen, C₁₋₃ alkyl or    C₁₋₃alkoxyC₂₋₃alkyl);-   6) C₁₋₅alkylR^(19a) (wherein R^(19a) is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear one    or two substituents selected from halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); and-   7) (CH₂)_(na)R^(20a) (wherein na is an integer from 0 to 5 and    R^(20a) is a phenyl group or a 5 or 6 membered aromatic heterocyclic    group with 1 to 3 heteroatoms selected from O, N and S, which phenyl    or aromatic heterocyclic group may carry up to 5 substituents    selected from halogeno, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,    C₁₋₄hydroxyalkoxy, carboxy, cyano, CONR^(21a)R^(21a) and    NR^(23a)COR^(24a) (wherein R^(21a), R^(22a), R^(23a) and R^(24a),    which may be the same or different, each represents hydrogen or    C₁₋₄alkyl)];    and salts thereof in the manufacture of a medicament for use in the    production of an antiangiogenic and/or vascular permeability    reducing effect in a warm-blooded animal such as a human being.

In a particular embodiment of the present invention there is provided amethod for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula Ia, as defined hereinbefore, or a pharmaceutically acceptablesalt thereof.

-   Z^(a) is advantageously —S—, preferably —O—, but especially —NH—.-   ma is advantageously an integer from 2 to 5, preferably 2 or 3,    especially 3.-   R^(1a) is advantageously hydrogen, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy or    amino.-   R^(1a) is preferably hydrogen, hydroxy, methyl, ethyl, methoxy or    ethoxy, more preferably hydrogen, hydroxy, methyl or methoxy but    especially methoxy.-   R^(2a) is preferably hydrogen, amino or nitro, but especially    hydrogen.

In one embodiment of the present invention R^(3a) represents hydroxy,halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, trifluoromethyl, cyano, amino or nitro.

Advantageously in another embodiment of the present invention one R^(3a)substituent is meta-hydroxy and the other one or more are each selectedfrom halogeno, methyl and methoxy.

In another embodiment of the invention the phenyl group bearing(R^(3a))_(ma) is preferably of the formula IIaa:

wherein:

-   R^(aa) represents hydrogen, methyl, fluoro or chloro, preferably    hydrogen, fluoro or chloro, especially fluoro;-   R^(ba) represents hydrogen, methyl, methoxy, bromo, fluoro or    chloro;-   R^(ca) represents hydrogen or hydroxy, especially hydroxy;-   R^(da) represents hydrogen, fluoro or chloro, especially fluoro.

Preferably in another embodiment of the invention two R^(3a)substituents are halogeno, especially ortho, ortho-difluoro, and theother one or more are each selected from halogeno and methyl.

In a particular aspect of the present invention, the phenyl groupbearing (R^(3a))_(ma) is the 2-fluoro-5-hydroxy-4-methylphenyl group,the 4-chloro-2-fluoro-5-hydroxyphenyl group, the4-bromo-2,6-difluorophenyl group, the 4-chloro-2,6-difluorophenyl groupor the 4-chloro-2-fluorophenyl group.

-   X^(1a) is preferably —O—.

Conveniently R^(4a) is selected from one of the following seven groups:

-   1) C₁₋₅alkyl, C₂₋₅hydroxyalkyl, C₁₋₅fluoroalkyl, C₂₋₅aminoalkyl;-   2) C₂₋₃alkylX^(2a)COR^(9a) (wherein X^(2a) represents —O— or NR^(8a)    (wherein R^(8a) represents hydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl)    and R^(9a) represents NR^(10a)R^(11a) or OR^(12a) (wherein R^(10a),    R^(11a) and R^(12a) which may be the same or different are each    C₁₋₂alkyl or C₁₋₂alkoxyethyl) with the proviso that when X^(2a) is    —O—, R^(9a) is not OR^(12a));-   3) C₂₋₄alkylX^(3a)R^(14a) (wherein X^(3a) represents —O—, —S—, —SO—,    —SO₂— or NR^(13a) (wherein R^(13a) is hydrogen, C₁₋₃alkyl or    C₁₋₂alkoxyethyl) and R^(14a) represents C₁₋₃alkyl, cyclopentyl or    cyclohexyl);-   4) C₂₋₃alkylX^(4a)C₂₋₃alkylX^(5a)R^(15a) (wherein X^(4a) and X^(5a)    which may be the same or different are each —O—, —S—, or NR^(16a)    (wherein R^(16a) is hydrogen or C₁₋₃alkyl) and R^(15a) represents    hydrogen or C₁₋₃alkyl);-   5) C₁₋₄alkylsulphonylNR^(17a)R^(18a) (wherein R^(17a) and R^(18a)    which may be the same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₂alkoxyethyl);-   6) C₁₋₅alkylR^(25a) (wherein R^(25a) is a 5 or 6 membered saturated    heterocyclic group with one or two heteroatoms, selected    independently from O, S and N, which heterocyclic group is linked to    C₁₋₅alkyl through a carbon atom and which heterocyclic group may    bear one or two substituents selected from halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy) or C₂₋₅alkylR^(26a) (wherein    R^(26a) is a 5 or 6 membered saturated heterocyclic group with one    or two heteroatoms of which one is N and the other is selected    independently from O, S and N, which heterocyclic group is linked to    C₂₋₅alkyl through a nitrogen atom and which heterocyclic group may    bear one or two substituents selected from halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); and-   7) (CH₂)_(na)R^(20a) (wherein na is an integer from 0 to 4 and    R^(20a) is a phenyl group or a 5 or 6 membered aromatic heterocyclic    group with 1 to 3 heteroatoms selected from O, N and S, of which    preferably one is N, which phenyl or aromatic heterocyclic group may    be substituted as hereinbefore defined, advantageously substituted    with up to 2 substituents as hereinbefore defined, more preferably    substituted with one substituent selected from the group of    substituents as hereinbefore defined).

Advantageously R^(4a) is selected from one of the following sevengroups:

-   1) C₁₋₄alkyl, C₂₋₄hydroxyalkyl, C₁₋₄fluoroalkyl, C₂₋₄aminoalkyl;-   2) C₂₋₃alkylX^(2a)COR^(9a) (wherein X^(2a) represents —O— or NR^(8a)    (wherein R^(8a)represents hydrogen, C₁₋₃alkyl or C₁₋₂alkoxyethyl)    and R^(9a) represents NR^(10a)R^(11a) or OR^(12a) (wherein R^(10a),    R^(11a) and R^(12a) which may be the same or different are each    C₁₋₂alkyl or C₁₋₂alkoxyethyl) with the proviso that when X^(2a) is    —O—, R^(9a) is not OR^(12a));-   3) C₂₋₄alkylX^(3a)R^(14a) (wherein X^(3a) represents —O—, —S—, —SO—,    —SO₂— or NR^(13a) (wherein R^(13a) is hydrogen, C₁₋₃alkyl or    C₁₋₂alkoxyethyl) and R^(14a) represents C₁₋₃alkyl, cyclopentyl or    cyclohexyl);-   4) C₂₋₃alkylX^(4a)C₂₋₃alkylX^(5a)R^(15a) (wherein X^(4a) and X^(5a)    which may be the same or different are each —O—, —S—, or NR^(16a)    (wherein R^(16a) is hydrogen or C₁₋₃alkyl) and R^(15a) represents    hydrogen or C₁₋₃alkyl);-   5) C₁₋₄alkylsulphonylNR^(17a)R^(18a) (wherein R^(17a) and R^(18a)    which may be the same or different are each hydrogen, C₁₋₃alkyl or    C₁₋₂alkoxyethyl);-   6) C₁₋₄alkylR^(25a) (wherein R^(25a) is selected from pyrrolidinyl,    piperazinyl, piperidyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl and 1,3-dithian-2-yl, such that R^(25a) is linked    to C₁₋₄alkyl through a carbon atom) or C₂₋₄alkylR^(26a) (wherein    R^(26a) is selected from morpholino, pyrrolidin-1-yl, piperazin-1-yl    and piperidino); and-   7) (CH₂)_(na)R^(20a) (wherein na is an integer from 1 to 3 and    R^(20a) is a 5 or 6 membered aromatic heterocyclic group with 1 to 2    heteroatoms selected from O, N and S, of which preferably one is N,    which aromatic heterocyclic group may be substituted as hereinbefore    defined, preferably substituted with one substituent selected from    halogeno, C₁₋₂alkyl, C₁₋₂alkoxy, C₁₋₂hydroxyalkyl,    C₁₋₂hydroxyalkoxy, carboxy, cyano, CONR^(21a)R^(22a) and    NR^(23a)COR^(24a) (wherein R^(21a), R^(22a), R^(23a) and R^(24a),    which may be the same or different, each represents hydrogen or    C₁₋₂alkyl)).

Preferably R^(4a) is selected from one of the following seven groups:

-   1) C₁₋₃alkyl, C₂₋₃hydroxyalkyl, C₁₋₃fluoroalkyl, C₂₋₃aminoalkyl;-   2) 2-(3,3-dimethylureido)ethyl, 3-(3,3-dimethylureido)propyl,    2-(3-methylureido)ethyl, 3-(3-methylureido)propyl, 2-ureidoethyl,    3-ureidopropyl, 2-(N,N-dimethylcarbamoyloxy)ethyl,    3-(N,N-dimethylcarbamoyloxy)propyl, 2-(N-methylcarbamoyloxy)ethyl,    3-(N-methylcarbamoyloxy)propyl, 2-(carbamoyloxy)ethyl,    3-(carbamoyloxy)propyl;-   3) C₂₋₃alkylX^(3a)R^(14a) (wherein X^(3a) represents —O—, —S—, —SO—,    —SO₂— or NR^(13a) (wherein R^(13a) is hydrogen, C₁₋₂alkyl or    C₁₋₂alkoxyethyl) and R^(14a) represents C₁₋₂alkyl, cyclopentyl or    cyclohexyl);-   4) C₁₋₃alkylX^(4a)C₂₋₃alkylX^(5a)R^(15a) (wherein X^(4a) and X^(5a)    which may be the same or different are each —O—, or —NH— and R^(15a)    represents hydrogen or C₁₋₂alkyl);-   5) C₁₋₃alkylsulphonylNR^(17a)R^(18a) (wherein R^(17a) and R^(18a)    which may be the same or different are each hydrogen or methyl);-   6) C₁₋₂alkylR^(25a) (wherein R^(25a) is selected from pyrrolidinyl,    piperazinyl, piperidyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl,    1,3-dithiolan-2-yl and 1,3-dithian-2-yl, such that R^(25a) is linked    to C₁₋₂alkyl through a carbon atom) or C₂₋₃alkylR^(26a) (wherein    R^(26a) is selected from morpholino, piperidino, piperazin-1-yl and    pyrrolidin-1-yl); and-   7) (CH₂)_(na)R^(20a) (wherein na is an integer from 1 to 3 and    R^(20a) is selected from pyridyl, imidazolyl, thiazolyl, thienyl and    pyridazinyl, preferably from pyridyl, imidazolyl and thiazolyl and    R^(20a) may be substituted with one substituent selected from    halogeno, C₁₋₂alkyl, C₁₋₂alkoxy, C₁₋₂hydroxyalkyl,    C₁₋₂hydroxyalkoxy, carboxy, cyano, CONR^(21a)R^(22a) and    NR^(23a)COR^(24a) (wherein R^(21a), R^(22a), R^(23a) and R^(24a),    which may be the sane or different, each represents hydrogen or    C₁₋₂alkyl), more preferably substituted with one substituent    selected from halogeno, C₁₋₂alkyl and cyano, especially substituted    with one substituent selected from chloro, fluoro, methyl and    ethyl).

More preferably R^(4a) represents methyl, ethyl, trifluoromethyl,2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl,3-methoxypropyl, 2-(methylsulphinyl)ethyl, 2-(methylsulphonyl)ethyl,2-(N,N-dimethylsulphamoyl)ethyl, 2-(N-methylsulphamoyl)ethyl,2-sulphamoylethyl, 2-(N,N-dimethylamino)ethyl,3-(N,N-dimethylamino)propyl, 2-morpholinoethyl, 3-morpholinopropyl,2-piperidinoethyl, 3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl or3-(4-pyridyl)propyl.

In a further embodiment of the present invention there is provided acompound of the formula Ia as defined hereinbefore with the proviso thatwhere ma is 1, R^(3a) is meta-hydroxy and with the further proviso thatthe compound of formula Ia is not4-(2,6-dimethylphenoxy)-6,7-dimethoxycinnoline; and salts thereof, foruse as a medicament.

As indicated above for a compound of formula Ia, as definedhereinbefore, and salts thereof, for use as a medicament:

-   ma is advantageously an integer from 2 to 5, preferably 2 or 3,    especially 3;-   Z^(a) is preferably —NH—;-   X^(1a) is preferably —O—; and-   preferably R^(4a) represents methyl, ethyl, trifluoromethyl,    2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,    2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,    2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,    2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,    2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,    2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,    3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,    3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,    3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,    2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,    2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,    3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,    1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl or    3-(4-pyridyl)propyl.

In a further embodiment of the present invention there is provided acompound of the formula Ia as defined hereinbefore with the proviso thatwhere ma is 1, R^(3a) is meta-hydroxy and with the further proviso thatthe phenyl group bearing (R^(3a))_(ma) is not 3,4-dimethylphenyl andthat when the phenyl group bearing (R^(3a))_(ma) is 2,5-dichlorophenyl,3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,2-bromo-4-chlorophenyl, 4-bromo-2-chlorophenyl, 2-bromo-4-methylphenyl,2-chloro-4-methylphenyl, 2-chloro-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 3,5-dichloro-4-hydroxyphenyl,2,5-dichloro-4-hydroxyphenyl or 5-chloro-2-methylphenyl, Z^(a) is —NH—;and salts thereof.

In a further embodiment of the present invention there is provided acompound of the formula Ia as defined hereinbefore with the proviso thatwhere ma is 1, R^(3a) is meta-hydroxy and with the further proviso thatthe phenyl group bearing (R^(3a))_(ma) is not 3,4-dimethylphenyl andthat when the phenyl group bearing (R^(3a))_(ma) is 2,5-dichlorophenyl,3,5-dichlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl,3,4-dimethoxyphenyl, 2-bromo-4-chlorophenyl, 4-bromo-2-chlorophenyl,2-bromo-4-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,3,5-dichloro-4-hydroxyphenyl, 2,5-dichloro-4-hydroxyphenyl or5-chloro-2-methylphenyl, Z^(a) is —NH—; and salts thereof.

As indicated above for a compound of formula Ia, as definedhereinbefore, and salts thereof:

-   ma is advantageously an integer from 2 to 5, preferably 2 or 3,    especially 3;-   Z^(a) is preferably —NH—;-   X^(1a) is preferably —O—; and-   preferably R^(4a) represents methyl, ethyl, trifluoromethyl,    2,2,2-trifluoroethyl, 2-hydroxyethyl, 3-hydroxypropyl,    2-methoxyethyl, 3-methoxypropyl, 2-(methylsulphinyl)ethyl,    2-(methylsulphonyl)ethyl, 2-(N,N-dimethylsulphamoyl)ethyl,    2-(N-methylsulphamoyl)ethyl, 2-sulphamoylethyl,    2-(N,N-dimethylamino)ethyl, 3-(N,N-dimethylamino)propyl,    2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl,    3-piperidinopropyl, 2-(piperazin-1-yl)ethyl,    3-(piperazin-1-yl)propyl, 2-(pyrrolidin-1-yl)ethyl,    3-(pyrrolidin-1-yl)propyl, (1,3-dioxolan-2-yl)methyl,    2-(1,3-dioxolan-2-yl)ethyl, 2-(2-methoxyethylamino)ethyl,    2-(2-hydroxyethylamino)ethyl, 3-(2-methoxyethylamino)propyl,    3-(2-hydroxyethylamino)propyl, 2-methylthiazol-4-ylmethyl,    1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl or    3-(4-pyridyl)propyl.

In a further particular embodiment of the current invention there isprovided a compound of the formula Ib:

[wherein R^(1b) is hydrogen, C₁₋₃alkoxy, preferably methoxy, orhalogeno, preferably chloro;

-   R^(2b) is hydrogen;-   X^(1b) is —O—;-   R^(4b) is C₁₋₃alkyl, 2-(C₁₋₃alkoxy)ethyl, benzyl,    4-pyridyl(C₁₋₃alkyl), morpholino(C₁₋₃alkyl), pyrrolidino(C₁₋₃alkyl),    2-methylthiazol-4-yl(C₁₋₃alkyl), 1-methylimidazol-2-yl(C₁₋₃alkyl)    and 2-((C₁₋₃alkoxy)(C₁₋₃alkoxy))ethyl;-   Z^(b) is —NH— or —O—;-   mb is 2 or 3; and-   the phenyl group bearing (R^(3b))_(mb) is selected from:    3-hydroxy-4-methylphenyl, 4-chloro-2-fluorophenyl,    4-bromo-2-fluorophenyl, 4-chloro-2-fluoro-5-hydroxyphenyl,    5-acetoxy-4-chloro-2-fluorophenyl, 2-fluoro-5-hydroxy-4-methylphenyl    and 4-bromo-2-fluoro-5-hydroxyphenyl]; and salts thereof.

Particularly preferred compounds of the present invention by virtue oftheir good activity against VEGF receptor tyrosine kinase activity andtheir lack of significant activity against epidermal growth factor (EGF)receptor tyrosine kinase include:

-   4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,-   4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline,    and especially the salts thereof, particularly the hydrochloride    salts thereof.    Another particularly preferred compound is    4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline    especially the salts thereof, particularly the hydrochloride salts    thereof.    Especially preferred compounds are:-   4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,-   4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline,-   4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline    and especially the salts thereof, particularly the hydrochloride    salts thereof.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsfor that group.

In this specification unless stated otherwise the term “alkyl” includesboth straight and branched chain alkyl groups but references toindividual alkyl groups such as “propyl” are specific for the straightchain version only. An analogous convention applies to other genericterms. Unless otherwise stated the term “alkyl” advantageously refers tochains with 1–6 carbon atoms, preferably 1–4 carbon atoms. The term“alkoxy” as used herein, unless stated otherwise includes“alkyl”-O-groups in which “alkyl” is as hereinbefore defined. The term“aryl” as used herein unless stated otherwise includes reference to aC₆₋₁₀aryl group which may, if desired, carry one or more substituentsselected from halogeno, alkyl, alkoxy, nitro, trifluoromethyl and cyano,(wherein alkyl and alkoxy are as hereinbefore defined). The term“aryloxy” as used herein unless otherwise stated includes“aryl”-O-groups in which “aryl” is as hereinbefore defined. The term“sulphonyloxy” as used herein refers to alkylsulphonyloxy andarylsulphonyloxy groups in which “alkyl” and “aryl” are as hereinbeforedefined. The term “alkanoyl” as used herein unless otherwise statedincludes alkylC═O groups in which “alkyl” is as defined hereinbefore,for example ethanoyl refers to CH₃C═O. In this specification unlessstated otherwise the term “alkenyl” includes both straight and branchedchain alkenyl groups but references to individual alkenyl groups such as2-butenyl are specific for the straight chain version only. Unlessotherwise stated the term “alkenyl” advantageously refers to chains with2–5 carbon atoms, preferably 3–4 carbon atoms. In this specificationunless stated otherwise the term “alkynyl” includes both straight andbranched chain alkynyl groups but references to individual alkynylgroups such as 2-butynyl are specific for the straight chain versiononly. Unless otherwise stated the term “alkynyl” advantageously refersto chains with 2–5 carbon atoms preferably 3–4 carbon atoms.

In formula I, as hereinbefore defined, hydrogen will be present atpositions 3 and 8 of the cinnoline group.

Within the present invention it is to be understood that a cinnoline ofthe formula I or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits VEGF receptor tyrosine kinase activity and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.

It is also to be understood that certain cinnolines of the formula I andsalts thereof can exist in solvated as well as unsolvated forms such as,for example, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which inhibit VEGF receptor tyrosinekinase activity.

For the avoidance of any doubt, it is to be understood that when X¹ is,for example, a group of formula —NR⁸CO—, it is the nitrogen atom bearingthe R⁸ group which is attached to the cinnoline ring and the carbonyl(CO) group is attached to R⁵, whereas when X¹ is, for example, a groupof formula —CONR⁹—, it is the carbonyl group which is attached to thecinnoline ring and the nitrogen atom bearing the R⁹ group is attached toR⁵. A similar convention applies to the other two atom X¹ linking groupssuch as —NR¹¹SO₂— and —SO₂NR¹⁰—. When X¹ is —NR¹²— it is the nitrogenatom bearing the R¹² group which is linked to the cinnoline ring and toR⁵. An analogous convention applies to other groups. It is further to beunderstood that when X¹ represents —NR¹²— and R¹² is C₁₋₃alkoxyC₂₋₃alkylit is the C₂₋₃alkyl moiety which is linked to the nitrogen atom of X¹and an analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of the formula I when R⁴ is a group R⁵—X¹ and R⁵ is, forexample, a group of formula (CH₂)_(n)R³¹, it is the terminal (CH₂)_(n)moiety which is bound to X¹, similarly when R⁵ is, for example, a groupof formula C₂₋₅alkenylR³¹ it is the C₂₋₅alkenyl moiety which is bound toX¹ and an analogous convention applies to other groups. When R⁵ is agroup 1-R³¹prop-1-en-3-yl it is the first carbon to which the group R³¹is attached and it is the third carbon which is linked to X¹ and ananalogous convention applies to other groups.

The present invention relates to the compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts of the invention may, for example, include acidaddition salts of the compounds of formula I as hereinbefore definedwhich are sufficiently basic to form such salts. Such acid additionsalts include for example salts with inorganic or organic acidsaffording pharmaceutically acceptable anions such as with hydrogenhalides (especially hydrochloric or hydrobromic acid of whichhydrochloric acid is particularly preferred) or with sulphuric orphosphoric acid, or with trifluoroacetic, citric or maleic acid. Inaddition where the compounds of formula I are sufficiently acidic,pharmaceutically acceptable salts may be formed with an inorganic ororganic base which affords a pharmaceutically acceptable cation. Suchsalts with inorganic or organic bases include for example an alkalimetal salt, such as a sodium or potassium salt, an alkaline earth metalsalt such as a calcium or magnesium salt, an ammonium salt or forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A compound of the formula I, or salt thereof, and other compounds of theinvention (as hereinafter defined) may be prepared by any process knownto be applicable to the preparation of chemically-related compounds.Such processes include, for example, those illustrated in EuropeanPatent Applications Publication Nos. 0520722, 0566226, 0602851 and0635498. Such processes, are provided as a further feature of theinvention and are as described hereinafter. Necessary starting materialsmay be obtained by standard procedures of organic chemistry. Thepreparation of such starting materials is described within theaccompanying non-limiting Examples. Alternatively necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist.

Thus the following processes (a) to (g) and (i) to (v) constitutefurther features of the present invention.

Synthesis of Compounds of Formula I

(a) Compounds of the formula I and salts thereof may be prepared by thereaction of a compound of the formula III:

(wherein R¹, R² and R⁴ are as defined hereinbefore and L¹ is adisplaceable moiety), with a compound of the formula IV:

(wherein Z, R³ and m are as defined hereinbefore) whereby to obtaincompounds of the formula I and salts thereof. A convenient displaceablemoiety L¹ is, for example, a halogeno, alkoxy (preferably C₁₋₄alkoxy),aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.

The reaction is advantageously effected in the presence of either anacid or a base. Such an acid is, for example, an anhydrous inorganicacid such as hydrogen chloride. Such a base is, for example, an organicamine base such as, for example, pyridine, 2,6-lutidine, collidine,4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholineor diazabicyclo[5.4.0]undec-7-ene, or for example, an alkali metal oralkaline earth metal carbonate or hydroxide, for example sodiumcarbonate, potassium carbonate, calcium carbonate, sodium hydroxide orpotassium hydroxide. Alternatively such a base is, for example, analkali metal hydride, for example sodium hydride, or an alkali metal oralkaline earth metal amide, for example sodium amide or sodiumbis(trimethylsilyl)amide. The reaction is preferably effected in thepresence of an inert solvent or diluent, for example an alkanol or estersuch as methanol, ethanol, isopropanol or ethyl acetate, a halogenatedsolvent such as methylene chloride, trichloromethane or carbontetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, anaromatic hydrocarbon solvent such as toluene, or a dipolar aproticsolvent such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction isconveniently effected at a temperature in the range, for example, 10 to150° C., preferably in the range 20 to 80° C.

The compound of the invention may be obtained from this process in theform of the free base or alternatively it may be obtained in the form ofa salt with the acid of the formula H-L¹ wherein L¹ has the meaningdefined hereinbefore. When it is desired to obtain the free base fromthe salt, the salt may be treated with a base as defined hereinbeforeusing a conventional procedure.

(b) Where the group of formula IIa:

(wherein R³ and m are as hereinbefore defined) represents a phenyl groupcarrying one or more hydroxy groups, a compound of the formula I andsalts thereof can be prepared by the deprotection of a compound offormula V:

(wherein m, R¹, R², R³, R⁴ and Z are as hereinbefore defined. Prepresents a phenolic hydroxy protecting group and p¹ is an integer from1 to 5 equal to the number of protected hydroxy groups and such thatm-p¹ is equal to the number of R³ substituents which are not protectedhydroxy). The choice of phenolic hydroxy protecting group P is withinthe standard knowledge of an organic chemist, for example those includedin standard texts such as “Protective Groups in Organic Synthesis” T. W.Greene and R. G. M. Wuts, 2nd Ed. Wiley 1991, including ethers (forexample methyl, methoxymethyl, allyl and benzyl), silyl ethers (forexample, t-butyldiphenylsilyl and t-butyldimethylsilyl), esters (forexample, acetate and benzoate) and carbonates (for example, methyl andbenzyl). The removal of such a phenolic hydroxy protecting group may beeffected by any of the procedures known for such a transformation,including those reaction conditions indicated in standard texts such asthat indicated hereinbefore, or by a related procedure. The reactionconditions preferably being such that the hydroxy derivative is producedwithout unwanted reactions at other sites within the starting or productcompounds. For example, where the protecting group P is acetate, thetransformation may conveniently be effected by treatment of thecinnoline derivative with a base as defined hereinbefore and includingammonia, and its mono and di-alkylated derivatives, preferably in thepresence of a protic solvent or co-solvent such as water or an alcohol,for example methanol or ethanol. Such a reaction can be effected in thepresence of an additional inert solvent or diluent as definedhereinbefore and at a temperature in the range 0 to 50° C., convenientlyat about 20° C.

(c) Production of those compounds of formula I and salts thereof whereinthe substituent R⁴ represents R⁵—X¹ and X¹ is —O—, —S— or —NR¹²—(wherein R¹² is as hereinbefore defined) can be achieved by thereaction, conveniently in the presence of a base as definedhereinbefore, of a compound of the formula VI:

(wherein m, X¹, R¹, R², R³, and Z are as hereinbefore defined) with acompound of formula VII:R⁵-L¹  (VII)(wherein R⁵ and L¹ are as hereinbefore defined); L¹ is a displaceablemoiety for example a halogeno or sulphonyloxy group such as a bromo ormethanesulphonyloxy group. The reaction is preferably effected in thepresence of a base (as defined hereinbefore in process (a)) andadvantageously in the presence of an inert solvent or diluent (asdefined hereinbefore in process (a)), advantageously at a temperature inthe range, for example 10 to 150° C., conveniently at about 50° C.

(d) Compounds of the formula I and salts thereof wherein the substituentR⁴ represents R⁵—X¹ may be prepared by the reaction of a compound of theformula VIII:

with a compound of the formula IX:R⁵—X¹—H  (IX)(wherein L¹, R¹, R², R³ R⁵, Z, m and X¹ are all as hereinbeforedefined). The reaction may conveniently be effected in the presence of abase (as defined hereinbefore in process (a)) and advantageously in thepresence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), advantageously at a temperature in the range, for example10 to 150° C., conveniently at about 100° C.

(e) Compounds of the formula I and salts thereof wherein R⁴ representsR⁵—X¹ and R⁵ is C₁₋₅alkylR⁶⁴, [wherein R⁶⁴ is selected from one of thefollowing four groups:

-   1) X¹⁰C₁₋₃alkyl (wherein X¹⁰ represents —O—, —S—, —SO₂—, NR⁶⁵CO,    NR⁶⁶SO₂ or NR⁶⁷ (wherein R⁶⁵, R⁶⁶ and R⁶⁷ each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   2) NR⁶⁸R⁶⁹ (wherein R⁶⁸ and R⁶⁹ which may be the same or different    are each hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl);-   3) X¹¹C₁₋₅alkylX⁵R²⁴ (wherein X¹¹ is —O—, —S—, —SO₂—, NR⁷⁰CO,    NR⁷¹SO₂ or NR72 (wherein R⁷⁰, R⁷¹ and R⁷² each independently    represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and X⁵ and    R²⁴ are as defined hereinbefore); and-   4) an aromatic heterocyclic group selected from pyrrolyl,    imidazolyl, pyrazolyl and triazolyl (which aromatic heterocyclic    group is linked to the C₁₋₅alkyl moiety via a nitrogen atom of the    heterocyclic ring and which aromatic heterocyclic group may carry up    to 4 substituents selected from halogeno, C₁₋₄alkyl, C₁₋₄alkoxy,    C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy, carboxy, cyano, CONR⁷³R⁷⁴ and    NR⁷⁵COR⁷⁶ (wherein R⁷³, R⁷⁴, R⁷⁵ and R⁷⁶, which may be the same or    different, each represents hydrogen or C₁₋₄alkyl)), or a 5 or 6    membered saturated heterocyclic group with one or two heteroatoms,    of which one is nitrogen and the other one may be selected    independently from O, S and N, (which heterocyclic group is linked    to the C₁₋₅alkyl moiety via a nitrogen atom of the heterocyclic    group and which heterocyclic group may bear one or two substituents    selected from halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and    C₁₋₄alkoxy)], may be prepared by reacting a compound of the formula    X:

(wherein L¹, X¹, R¹, R², R³, Z and m are as hereinbefore defined and R⁷⁷is C₁₋₅alkyl) with a compound of the formula XI:R⁶⁴—H  (XI)(wherein R⁶⁴ is as defined hereinbefore) to give a compound of theformula I. The reaction may conveniently be effected in the presence ofa base (as defined hereinbefore in process (a)) and advantageously inthe presence of an inert solvent or diluent (as defined hereinbefore inprocess (a)), and at a temperature in the range, for example 0 to 150°C., conveniently at about 50° C.

(f) The production of those compounds of the formula I and salts thereofwherein the substituent R¹ is represented by NR⁶R⁷, where one or both ofR⁶ and R⁷ are C₁₋₃alkyl, may be effected by the reaction of compounds offormula I wherein the substituent R¹ is an amino group and an alkylatingagent, preferably in the presence of a base as defined hereinbefore.Such alkylating agents are C₁₋₃alkyl moieties bearing a displaceablemoiety as defined hereinbefore such as C₁₋₃alkyl halides for exampleC₁₋₃alkyl chloride, bromide or iodide. The reaction is preferablyeffected in the presence of an inert solvent or diluent (as definedhereinbefore in process (a)) and at a temperature in the range, forexample, 10 to 100° C. conveniently at about ambient temperature. Thisprocess can also be used for preparing compounds in which R⁵—X¹ is analkylamino or dialkylamino group.

(g) The production of compounds of formula I and salts thereof whereinone or more of the substituents R¹, R² or R³ is an amino group or whereR⁵—X¹ is amino may be effected by the reduction of a correspondingcompound of formula I wherein the substituent(s) at the correspondingposition(s) of the cinnoline and/or phenyl ring is/are a nitro group(s).The reduction may conveniently be effected as described in process (i)hereinafter. The production of a compound of formula I and salts thereofwherein the substituent(s) at the corresponding position(s) of thecinnoline and/or phenyl ring is/are a nitro group(s) may be effected bythe processes described hereinbefore and hereinafter in processes (a–e)and (i–v) using a cinnoline compound selected from the compounds of theformulae (I–XXVIII) in which the substituent(s) at the correspondingposition(s) of the cinnoline and/or phenyl ring is/are a nitro group(s).

Synthesis of Intermediates

(i) The compounds of formula III and salts thereof, constitute a furtherfeature of the present invention. Such compounds in which L¹ is halogenomay for example be prepared by halogenating a compound of the formulaXII:

(wherein R¹, R² and R⁴ are as hereinbefore defined).

Convenient halogenating agents include inorganic acid halides, forexample thionyl chloride, phosphorus(III)chloride,phosphorus(V)oxychloride and phosphorus(V)chloride. The halogenationreaction is conveniently effected in the presence of an inert solvent ordiluent such as for example a halogenated solvent such as methylenechloride, trichloromethane or carbon tetrachloride, or an aromatichydrocarbon solvent such as benzene or toluene. The reaction isconveniently effected at a temperature in the range, for example 10 to150° C., preferably in the range 40 to 100° C.

The compounds of formula XII and salts thereof which constitute afurther feature of the present invention may for example be prepared byreacting a compound of the formula XIII:

(wherein R¹, R² and L¹ are as hereinbefore defined) with a compound ofthe formula IX as hereinbefore defined. The reaction may conveniently beeffected in the presence of a base (as defined hereinbefore in process(a)) and advantageously in the presence of an inert solvent or diluent(as defined hereinbefore in process (a)), advantageously at atemperature in the range, for example 10 to 150° C., conveniently atabout 100° C.

The compounds of formula XII and salts thereof may also be prepared bycyclising a compound of the formula XIV:-

(wherein R¹, R² and R⁴ are as hereinbefore defined) whereby to form acompound of formula XII or salt thereof. The cyclisation may beconveniently effected in the presence of a mineral or organic acid, forexample sulphuric acid, hydrochloric acid or acetic acid or a mixturethereof, preferably at a temperature in the range 20° C. to 100° C.,especially 50–80° C. or if desired under pH-controlled conditions,advantageously at a pH of 4.0 to 8.5. Preferably the pH of the solutionis maintained within the range of 6.5 to 8.0. The desired pH isconveniently obtained by the use of an inert base or by the use of anaqueous solution of such a base. Bases which may be used include alkalimetal bicarbonates, carbonates or hydroxides or organic amines such asfor example pyridine or tertiary amines such as triethylamine,diisopropylethylamine, 2,6-lutidine, collidine, 4-dimethylaminopyridineor methylmorpholine [for example as described in U.S. Pat. No. 4,620,000(L. R. Denes) or DD 258809 (Hirsch et al.]

The compounds of formula XIV and salts thereof, which constitute afurther feature of the present invention, may for example be prepared bydiazotisation of a compound of the formula XV:-

(wherein R¹, R² and R⁴ are as hereinbefore defined). The diazotisationis conveniently effected by the use of an alkali metal nitrite, such assodium nitrite, in the presence of a mineral acid such as hydrochloricor sulphuric acid or in the presence of an organic acid such as aceticacid or in the presence of a mixture of such acids. The diazotisation isadvantageously effected at a temperature in the range between thefreezing point of the reaction mixture and 20° C., preferably from 0 to20° C.

Preferably the compounds of formula XII are prepared by diazotisationand in situ cyclisation of the resulting compound of formula XIV forexample as described by Borsch W. and Herbert A. Annalen der Chemie,Volume 546, p 293–303.

Compounds of formula XV and salts thereof, which constitute a furtherfeature of the present invention, may for example be prepared byreduction of the nitro group in a compound of formula XVI:

(wherein R¹, R² and R⁴ are as hereinbefore defined) to yield a compoundof formula XV as hereinbefore defined or salt thereof. The reduction ofthe nitro group may conveniently be effected by any of the proceduresknown for such a transformation. The reduction may be carried out, forexample, by hydrogenation of a solution of the nitro compound in thepresence of an inert solvent or diluent as defined hereinbeforepreferably in the presence of a metal hydrogenation catalyst such aspalladium or platinum. A further reducing agent is, for example, anactivated metal such as activated iron (produced for example by washingiron powder with a dilute solution of an acid such as hydrochloricacid). Thus, for example, the reduction may be effected by heating amixture of the nitro compound and the activated metal in the presence ofa solvent or diluent such as a mixture of water and alcohol, for examplemethanol or ethanol, to a temperature in the range, for example, 50 to150° C., conveniently at about 70° C.

Where the reduction is effected in the presence of activated iron, thisis advantageously produced in situ, conveniently by the use of iron,generally iron powder, in the presence of acetic acid/water andpreferably at about 100° C.

The compounds of formula XVI and salts thereof which constitute afurther feature of the present invention may for example be produced byreacting a compound of formula XVII:

(wherein R¹, R² and L¹ are as hereinbefore defined) with a compound offormula IX as hereinbefore defined to yield a compound of formula XVI ashereinbefore defined or salt thereof. The reaction of the compounds offormula XVII and IX is conveniently effected under conditions asdescribed for process (d) hereinbefore.

Compounds of formula XVII and salts thereof may for example be preparedby nitration of a compound of the formula XVIII:-

(wherein R¹, R² and L¹ are as hereinbefore defined whereby to form acompound of formula XVIII as hereinbefore defined or a salt thereof. Thenitration is conveniently effected in the presence of nitric acid whichmay be dilute or concentrated, but is preferably about 70% nitric acid.The nitration is conveniently effected at a temperature in the range 0to 20° C. The nitration may also be effected in the presence of a Lewisacid catalyst such as tin(IV)chloride. Where a Lewis acid catalyst isused the reaction is advantageously effected at a lower temperature,conveniently in the range −50 to 0° C. preferably at about −30° C.,preferably in the presence of methylene chloride.

The compounds of formula XVI, as defined hereinbefore, and salts thereofmay for example be prepared by nitration of compound of the formulaXVIII in which the L¹ moiety is replaced by R⁴. The nitration isconveniently effected as described hereinbefore.

The compounds of formula XIII, as defined hereinbefore, and saltsthereof may for example be prepared from compounds of the formulae XIVand XV, in which the R⁴ group is replaced by the moiety L¹, thereactions may be effected by processes as described above for thepreparation of compounds of formula XII from a compounds of formulae XIVand XV. Compounds of the formula XV in which the R⁴ group is replaced bythe moiety L¹ may be prepared by the reduction of the nitro group incompounds of the formua XVII, the reduction may be effected as definedhereinbefore.

The compounds of formula III and salts thereof wherein R⁴ representsR⁵—X¹ may also be prepared for example by reacting a compound of theformula XIX:

(wherein R¹, R² and X¹ are as hereinbefore defined and L² represents adisplaceable protecting moiety) with a compound of the formula VII ashereinbefore defined whereby to obtain a compound of formula III inwhich L¹ is represented by L².

A compound of formula XIX is conveniently used in which L² represents aphenoxy group which may if desired carry up to 5 substituents,preferably up to 2 substituents, selected from halogeno, nitro andcyano. More preferably L² is chloro. The reaction may be convenientlyeffected under conditions as described for process (c) hereinbefore.

The compounds of formula XIX and salts thereof as hereinbefore definedmay for example be prepared by deprotecting a compound of formula XX:

(wherein R¹, R², P, X¹ and L² are as hereinbefore defined). Deprotectionmay be effected by techniques well known in the literature, for examplewhere P represents a benzyl group deprotection may be effected byhydrogenolysis, or by treatment with trifluoroacetic acid.

One compound of formula III may if desired be converted into anothercompound of formula III in which the moiety L¹ is different. Thus forexample a compound of formula III in which L¹ is other than halogeno,for example optionally substituted phenoxy, may be converted to acompound of formula III in which L¹ is halogeno by hydrolysis of acompound of formula III (in which L¹ is other than halogeno) to yield acompound of formula XII as hereinbefore defined, followed byintroduction of halide to the compound of formula XII, thus obtained ashereinbefore defined, to yield a compound of formula III in which L¹represents halogen.

(ii) The compounds of formula V and salts thereof, constitute a furtherfeature of the present invention, and may for example be prepared by thereaction of a compound of formula III as hereinbefore defined with acompound of the formula XXI:

(wherein R³, m, p¹, P and Z are as hereinbefore defined), whereby toform a compound of formula V as hereinbefore defined or a salt thereof.The reaction may for example be effected as described for process (a)hereinbefore.

The compounds of formula V and salts thereof wherein R⁴ represents R⁵—X¹may also be prepared by reacting a compound of formula XXII:

(wherein R¹, R², L¹, Z, R³, m, p¹ and P are as hereinbefore defined)with a compound of formula IX as hereinbefore defined, whereby to form acompound of formula V as hereinbefore defined or a salt thereof. Thereaction may for example be effected as described for process (d) above.

The compounds of formula V and salts thereof wherein R⁴ represents R⁵—X¹may also be prepared by reacting a compound of formula XXIII:

(wherein R¹, R², R³, X¹, Z, P, p¹ and m are as hereinbefore defined)with a compound of the formula VII as hereinbefore defined, whereby toform a compound of formula V as hereinbefore defined or a salt thereof.The reaction may for example be effected as described for process (c)hereinbefore.

The compounds of formula XXII and salts thereof, which constitute afurther feature of the present invention, may for example be prepared byreaction of a compound of formula XXIV:

(wherein R¹, R², and L¹ are as hereinbefore defined, and L¹ in the 4-and 7-positions may be the same or different) with a compound of theformula XXI as hereinbefore defined whereby to form a compound offormula XXII as hereinbefore defined or a salt thereof. The reaction maybe effected for example by a process as described in (a) above.

Compounds of the formulae XX and XXIV may be prepared by any convenientknown method, but may for example be prepared by introducing the moietyL² or L¹ as hereinbefore defined into a compound corresponding to acompound of formula XII but in which the group R⁴ is replaced by themoiety P—X¹ or L¹. The reaction may be effected for example by a processas described for the preparation of compounds of formula III fromcompounds of formula XII as described in (i) above.

Compounds of the formula XXIII and salts thereof, which constitute afurther feature of the present invention, may be made by deprotecting acompound of formula XXV:

(wherein R¹, R², R³, P, Z, X¹, p¹ and m are as hereinbefore defined)whereby to form a compound of formula XXIII or salt thereof.Deprotection of the compound of formula XXV may for example be effectedas described in (i) above.

The compounds of formula XXV and salts thereof constitute a furtherfeature of the present invention and may be prepared, for example, byreacting a compound of formula XX as hereinbefore defined with acompound of formula XXI as hereinbefore defined. The reaction may forexample be effected as described in process (a).

Compounds of the formula V, as hereinbefore defined, and salts thereofwherein R⁴ represents R⁵—X¹ and R⁵ is C₁₋₅alkylR⁶⁴, wherein R⁶⁴ is ashereinbefore defined, may also be prepared by the reaction of a compoundof formula XXVI:

(wherein L¹, R⁷⁷, X¹, R¹, R², R³, Z, P, m and p¹ are as definedhereinbefore) with a compound of the formula XI as defined hereinbefore,under the conditions described in (e) above.

Compounds of the formula XXVI and salts thereof, which constitute afurther feature of the present invention, may be made for example byreacting compounds of the formulae XXIII as defined hereinbefore, with acompound of the formula XXVII:L¹-R⁷⁷-L¹  (XXVII)(wherein L¹ and R⁷⁷ are as hereinbefore defined) under the conditionsdescribed in (c) above.

(iii) Compounds of the formula VI, as hereinbefore defined, and saltsthereof constitute a further feature of the present invention and may beprepared by deprotecting the compound of formula XXVIII:

(wherein R¹, R², R³, P, Z, X¹ and m are as hereinbefore defined) forexample by a process as described in (i) above.

Compounds of the formula XXVIII and salts thereof, which constitute afurther feature of the present invention, may for example be prepared byreacting compounds of the formulae XX and IV as hereinbefore defined,advantageously under the conditions described in (a) hereinbefore, togive a compound of the formula XXVIII as hereinbefore defined or saltthereof.

(iv) Compounds of the formula VIII as hereinbefore defined and saltsthereof which constitute a further feature of the present invention mayfor example be prepared by reacting compounds of the formulae XXIV andIV as hereinbefore defined, the reaction may for example be effected bya process as described in (a) above.

(v) Compounds of the formula X as defined hereinbefore and salts thereofconstitute a further feature of the present invention and may forexample be made by reacting compounds of the formulae VI and XXVII asdefined hereinbefore, the reaction may be effected for example by aprocess as described in (c) above.

Compounds of the formula X and salts thereof may also be made forexample by deprotecting a compound of the formula XXVI, as hereinbeforedefined, by a process for example as described in (b) above.

When a pharmaceutically acceptable salt of a compound of the formula Iis required, it may be obtained, for example, by reaction of saidcompound with, for example, an acid using a conventional procedure, theacid having a pharmaceutically acceptable anion.

Many of the intermediates defined herein are novel, for example, thoseof the formulae III, V, VI, X, XII, XIV, XV, XVI, XXII, XXIII, XXV, XXVIand XXVIII and these are provided as a further feature of the invention.

The identification of compounds which potently inhibit the tyrosinekinase activity associated with the VEGF receptors such as Flt and/orKDR and which inhibit angiogenesis and/or increased vascularpermeability is desirable and is the subject of the present invention.These properties may be assessed, for example, using one or more of theprocedures set out below:

(a) In Vitro Receptor Tyrosine Kinase Inhibition Test

This assay determines the ability of a test compound to inhibit tyrosinekinase activity. DNA encoding VEGF or epidermal growth factor (EGF)receptor cytoplasmic domains may be obtained by total gene synthesis(Edwards M, International Biotechnology Lab 5(3), 19–25, 1987) or bycloning. These may then be expressed in a suitable expression system toobtain polypeptide with tyrosine kinase activity. For example VEGF andEGF receptor cytoplasmic domains, which were obtained by expression ofrecombinant protein in insect cells, were found to display intrinsictyrosine kinase activity. In the case of the VEGF receptor Flt (Genbankaccession number X51602), a 1.7 kb DNA fragment encoding most of thecytoplasmic domain, commencing with methionine 783 and including thetermination codon, described by Shibuya et al (Oncogene, 1990, 5:519–524), was isolated from cDNA and cloned into a baculovirustransplacement vector (for example pAcYM1 (see The BaculovirusExpression System: A Laboratory Guide, L. A. King and R. D. Possee,Chapman and Hall, 1992) or pAc360 or pBlueBacHis (available fromInvitrogen Corporation)). This recombinant construct was co-transfectedinto insect cells (for example Spodoptera frugiperda 21(Sf21)) withviral DNA (eg Pharmingen BaculoGold) to prepare recombinant baculovirus.(Details of the methods for the assembly of recombinant DNA moleculesand the preparation and use of recombinant baculovirus can be found instandard texts for example Sambrook et al. 1989. Molecular cloning—ALaboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press andO'Reilly et al, 1992, Baculovirus Expression Vectors—A LaboratoryManual, W. H. Freeman and Co, New York). For other tyrosine kinases foruse in assays, cytoplasmic fragments starting from methionine 806 (KDR,Genbank accession number L04947) and methionine 668 (EGF receptor,Genbank accession number X00588) may be cloned and expressed in asimilar manner.

For expression of cFlt tyrosine kinase activity, Sf21 cells wereinfected with plaque-pure cFlt recombinant virus at a multiplicity ofinfection of 3 and harvested 48 hours later. Harvested cells were washedwith ice cold phosphate buffered saline solution (PBS) (10 mM sodiumphosphate pH7.4, 138 mM NaCl, 2.7 mM KCl) then resuspended in ice coldHNTG/PMSF (20 mM Hepes pH7.5, 150 mM NaCl, 10% v/v glycerol, 1% v/vTriton X100, 1.5 mM MgCl₂, 1 mM ethylene glycol-bis(βaminoethyl ether)N,N,N′,N′-tetraacetic acid (EGTA), 1 mM PMSF (phenylmethylsulphonylfluoride); the PMSF is added just before use from a freshly-prepared 100mM solution in methanol) using 1 ml HNTG/PMSF per 10 million cells. Thesuspension was centrifuged for 10 minutes at 13,000 rpm at 4° C., thesupernatant (enzyme stock) was removed and stored in aliquots at −70° C.Each new batch of stock enzyme was titrated in the assay by dilutionwith enzyme diluent (100 mM Hepes pH 7.4, 0.2 mM Na₃VO₄, 0.1% v/v TritonX100, 0.2 mM dithiothreitol). For a typical batch, stock enzyme isdiluted 1 in 2000 with enzyme diluent and 50 μl of dilute enzyme is usedfor each assay well.

A stock of substrate solution was prepared from a random copolymercontaining tyrosine, for example Poly (Glu, Ala, Tyr) 6:3:1 (SigmaP3899), stored as 1 mg/ml stock in PBS at −20° C. and diluted 1 in 500with PBS for plate coating.

On the day before the assay 100 μl of diluted substrate solution wasdispensed into all wells of assay plates (Nunc maxisorp 96-wellimmunoplates) which were sealed and left overnight at 4° C.

On the day of the assay the substrate solution was discarded and theassay plate wells were washed once with PBST (PBS containing 0.05% v/vTween 20) and once with 50 mM Hepes pH7.4.

Test compounds were diluted with 10% dimethylsulphoxide (DMSO) and 25 μlof diluted compound was transferred to wells in the washed assay plates.“Total” control wells contained 10% DMSO instead of compound. Twentyfive microlitres of 40 mM MnCl₂ containing 8 μMadenosine-5′-triphosphate (ATP) was added to all test wells except“blank” control wells which contained MnCl₂ without ATP. To start thereactions 50 μl of freshly diluted enzyme was added to each well and theplates were incubated at room temperature for 20 minutes. The liquid wasthen discarded and the wells were washed twice with PBST. One hundredmicrolitres of mouse IgG anti-phosphotyrosine antibody (UpstateBiotechnology Inc. product 05-321), diluted 1 in 6000 with PBSTcontaining 0.5% w/v bovine serum albumin (BSA), was added to each welland the plates were incubated for 1 hour at room temperature beforediscarding the liquid and washing the wells twice with PBST. One hundredmicrolitres of horse radish peroxidase (HRP)-linked sheep anti-mouse Igantibody (Amersham product NXA 931), diluted 1 in 500 with PBSTcontaining 0.5% w/v BSA, was added and the plates were incubated for 1hour at room temperature before discarding the liquid and washing thewells twice with PBST. One hundred microlitres of2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) solution,freshly prepared using one 50 mg ABTS tablet (Boehringer 1204 521) in 50ml freshly prepared 50 mM phosphate-citrate buffer pH5.0+0.03% sodiumperborate (made with a phosphate citrate buffer with sodium perborate(PCSB) capsule (Sigma P4922) per 100 ml distilled water), was added toeach well. Plates were then incubated for 20–60 minutes at roomtemperature until the optical density value of the “total” controlwells, measured at 405 nm using a plate reading spectrophotometer, wasapproximately 1.0. “Blank” (no ATP) and “total” (no compound) controlvalues were used to determine the dilution range of test compound whichgave 50% inhibtion of enzyme activity.

(b) In Vitro HUVEC Proliferation Assay

This assay determines the ability of a test compound to inhibit thegrowth factor-stimulated proliferation of human umbilical veinendothelial cells (HUVEC).

HUVEC cells were isolated in MCDB 131 (Gibco BRL)+7.5% v/v foetal calfserum (FCS) and were plated out (at passage 2 to 8), in MCDB 131+2% v/vFCS+3 μg/ml heparin+1 μg/ml hydrocortisone, at a concentration of 1000cells/well in 96 well plates. After a minimum of 4 hours they were dosedwith the appropriate growth factor (i.e. VEGF 3 ng/ml. EGF 3 ng/ml orb-FGF 0.3 ng/ml) and compound. The cultures were then incubated for 4days at 37° C. with 7.5% CO₂. On day 4 the cultures were pulsed with 1μCi/well of tritiated-thymidine (Amersham product TRA 61) and incubatedfor 4 hours. The cells were harvested using a 96-well plate harvester(Tomtek) and then assayed for incorporation of tritium with a Beta platecounter. Incorporation of radioactivity into cells, expressed as cpm,was used to measure inhibition of growth factor-stimulated cellproliferation by compounds.

(c) In Vivo Rat Uterine Oedema Assay

This test measures the capacity of compounds to reduce the acuteincrease in uterine weight in rats which occurs in the first 4–6 hoursfollowing oestrogen stimulation. This early increase in uterine weighthas long been known to be due to oedema caused by increased permeabilityof the uterine vasculature and recently Cullinan-Bove and Koos(Endocrinology, 1993, 133:829–837) demonstrated a close temporalrelationship with increased expression of VEGF mRNA in the uterus. Wehave found that prior treatment of the rats with a neutralisingmonoclonal antibody to VEGF significantly reduces the acute increase inuterine weight, confirming that the increase in weight is substantiallymediated by VEGF.

Groups of 20 to 22-day old rats were treated with a single subcutaneousdose of oestradiol benzoate (2.5 μg/rat) in a solvent, or solvent only.The latter served as unstimulated controls. Test compounds were orallyadministered at various times prior to the administration of oestradiolbenzoate. Five hours after the administration of oestradiol benzoate therats were humanely sacrificed and their uteri were dissected, blottedand weighed. The increase in uterine weight in groups treated with testcompound and oestradiol benzoate and with oestradiol benzoate alone wascompared using a Student T test. Inhibition of the effect of oestradiolbenzoate was considered significant when p<0.05.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula Ias defined hereinbefore or a pharmaceutically acceptable salt thereof,in association with a pharmaceutically acceptable excipient or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) forexample as a sterile solution, suspension or emulsion, for topicaladministration for example as an ointment or cream or for rectaladministration for example as a suppository. In general the abovecompositions may be prepared in a conventional manner using conventionalexcipients.

The compositions of the present invention are advantageously presentedin unit dosage form. The compound will normally be administered to awarm-blooded animal at a unit dose within the range 5–5000 mg per squaremetre body area of the animal, i.e. approximately 0.1–100 mg/kg. A unitdose in the range, for example, 1–100 mg/kg, preferably 1–50 mg/kg isenvisaged and this normally provides a therapeutically-effective dose. Aunit dose form such as a tablet or capsule will usually contain, forexample 1–250 mg of active ingredient.

According to a further aspect of the present invention there is provideda compound of the formula I or a pharmaceutically acceptable saltthereof as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy.

We have found that compounds of the present invention inhibit VEGFreceptor tyrosine kinase activity and are therefore of interest fortheir antiangiogenic effects and/or their ability to cause a reductionin vascular permeability.

Thus according to a further aspect of the invention there is providedthe use of a compound of the formula I, or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for use in theproduction of an antiangiogenic and/or vascular permeability reducingeffect in a warm-blooded animal such as a human being.

According to a further feature of the invention there is provided amethod for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal, such as a human being, in needof such treatment which comprises administering to said animal aneffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration andthe severity of the illness being treated. Preferably a daily dose inthe range of 1–50 mg/kg is employed. However the daily dose willnecessarily be varied depending upon the host treated, the particularroute of administration, and the severity of the illness being treated.Accordingly the optimum dosage may be determined by the practitioner whois treating any particular patient.

The antiangiogenic and/or vascular permeability reducing treatmentdefined hereinbefore may be applied as a sole therapy or may involve, inaddition to a compound of the invention, one or more other substancesand/or treatments. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate administration of the individualcomponents of the treatment. In the field of medical oncology it isnormal practice to use a combination of different forms of treatment totreat each patient with cancer. In medical oncology the othercomponent(s) of such conjoint treatment in addition to theantiangiogenic and/or vascular permeability reducing treatment definedhereinbefore may be: surgery, radiotherapy or chemotherapy. Suchchemotherapy may cover three main categories of therapeutic agent:

-   (i) other antiangiogenic agents that work by different mechanisms    from those defined hereinbefore (for example linomide, inhibitors of    integrin αvβ3 function, angiostatin, razoxin, thalidomide);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example anastrozole, letrazole, vorazole, exemestane),    antiprogestogens, antiandrogens (for example flutamide, nilutamide,    bicalutamide, cyproterone acetate), LHRH agonists and antagonists    (for example goserelin acetate, luprolide), inhibitors of    testosterone 5α-dihydroreductase (for example finasteride),    anti-invasion agents (for example metalloproteinase inhibitors like    marimastat and inhibitors of urokinase plasminogen activator    receptor function) and inhibitors of growth factor function, (such    growth factors include for example platelet derived growth factor    and hepatocyte growth factor such inhibitors include growth factor    antibodies, growth factor receptor antibodies, tyrosine kinase    inhibitors and serine/threonine kinase inhibitors), and-   (iii) antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as antimetabolites (for    example antifolates like methotrexate, fluoropyrimidines like    5-fluorouracil, purine and adenosine analogues, cytosine    arabinoside); antitumour antibiotics (for example anthracyclines    like doxorubicin, daunomycin, epirubicin and idarubicin,    mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for    example cisplatin, carboplatin); alkylating agents (for example    nitrogen mustard, melphalan, chlorambucil, busulphan,    cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic    agents (for example vinca alkaloids like vincrisitine and taxoids    like taxol, taxotere); topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan).

As stated above the compounds defined in the present invention are ofinterest for their antiangiogenic and/or vascular permeability reducingeffects. Such compounds of the invention are expected to be useful in awide range of disease states including cancer, diabetes, psoriasis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restenosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation. Inparticular such compounds of the invention are expected to slowadvantageously the growth of primary and recurrent solid tumours of, forexample, the colon, breast, prostate, lungs and skin. More particularlysuch compounds of the invention are expected to inhibit the growth ofthose primary and recurrent solid tumours which are associated withVEGF, especially those tumours which are significantly dependent on VEGFfor their growth and spread, including for example, certain tumours ofthe colon, breast, prostate, lung, vulva and skin.

In addition to their use in therapeutic medicine, the compounds offormula I and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof VEGF receptor tyrosine kinase activity in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents.

It is to be understood that where the term “ether” is used anywhere inthis specification it refers to diethyl ether.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:-

[(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18–25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) melting points are uncorrected and were determined using a MettlerSP62 automatic melting point apparatus, an oil-bath apparatus or aKoffler hot plate apparatus.

(vi) the structures of the end-products of the formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet: t, triplet; m, multiplet; br, broad; q,quartet:

(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(viii) petroleum ether refers to that fraction boiling between 40–60° C.

(ix) the following abbreviations have been used:-

-   -   DMF N,N-dimethylformamide    -   DMSO dimethylsulphoxide    -   TFA trifluoroacetic acid.]

EXAMPLE 1

A solution of 4-chloro-6,7-dimethoxycinnnoline hydrochloride (0.6 g, 2.3mmol), 3-hydroxy-4-methylaniline (0.425 g, 2.5 mmol) and triethylamine(800 μl, 6 mmol) in DMF (10 ml) was refluxed for 1 hour. The solutionwas cooled and poured directly onto a Diaion (trade mark of Mitsubishi)HP20SS column and elution was performed with acetonitrile/water (4/6) togive, after evaporation of the solvent,4-(3-hydroxy-4-methylanilino)-6,7-dimethoxycinnoline (220 mg, 31%) as acream solid.

m.p. 240–244° C. ¹H NMR Spectrum: (DMSOd₆) 2.15(s, 3H); 3.97(s, 3H);3.99(s, 3H); 6.73(d, 1H); 6.85(s, 1H); 7.14(d, 1H); 7.52(s, 1H); 7.69(s,1H); 8.73(s, 1H); 8.81(s, 1H); 9.6(s, 1H) MS-ESI: 312 [MH]⁺

Elemental analysis: Found C 62.2 H 5.8 N 13.1 C₁₇H₁₇N₃O₃ 0.9H₂O RequiresC 62.3 H 5.8 N 12.8%

The starting material, 4-chloro-6,7-dimethoxycinnoline hydrochloride wasobtained by heating a solution of 4-hydroxy-6,7-dimethoxycinnoline (1 g,4.8 mmol) in thionyl chloride (20 ml) containing DMF (2 drops) at refluxfor 3 hours. After cooling and evaporating the excess thionyl chloride,the solid was triturated with ether and filtered to give4-chloro-6,7-dimethoxycinnoline hydrochloride (1.2 g, quantitative).

The starting material, 4-hydroxy-6,7-dimethoxycinnoline was obtained byadding a solution of sodium nitrite (1.9 g, 27 mmol) to a solution of2-amino-4,5-dimethoxyacetophenone (5 g, 0.025 mol) in acetic acid (90ml) and sulphuric acid (15 ml) at a rate to maintain the temperaturebelow 20° C. The mixture was heated at 80° C. for 90 minutes. Aftercooling and concentrating the solution to half its original volume, theresidue was poured into ether (800 ml). The solid was collected byfiltration and suspended in water (200 ml). After adjusting to pH7 withsodium hydroxide the solid was filtered, washed with water, methanol andmethylene chloride to give 4-hydroxy-6,7-dimethoxycinnoline (4.5 g,87%).

EXAMPLE 2

A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g,1.5 mmol) and 3-hydroxy-4-methylaniline (0.2 g, 1.6 mmol) in DMF (5 ml)was heated at 150° C. for 20 minutes. After cooling, isopropanol (15 ml)was added and the resulting solid filtered off, washed with isopropanoland dried under vacuum to give4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline asthe hydrochloride salt (yellow solid, 537 mg 91%).

¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 2.38(s, 3H); 3.55(s, 3H); 3.95(t,2H); 4.2(s, 3H); 4.5(t, 2H); 7.05(d, 1H); 7.1(s, 1H); 7.4(d, 1H);7.52(s, 1H); 8.2(s, 1H); 8.55(d, 1H) MS-ESI: 356 [MH]⁺

Elemental analysis: Found C 58.4 H 5.9 N 10.9 C₁₉H₂₁N₃O₄ 1HCl Requires C58.2 H 5.7 N 10.7%

The starting material 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnolinewas obtained by heating a solution of4-hydroxy-6-methoxy-7-(2-methoxyethoxy)cinnoline (7.8 g, 0.031 mol) inthionyl chloride (130 ml) containing DMF (0.8 ml) at 80° C. for 2 hours.After dilution with toluene, the mixture was evaporated to dryness. Theresulting solid was filtered off, washed with ether, and then dissolvedin ethyl acetate. The ethyl acetate solution was washed with saturatedaqueous sodium hydrogen carbonate solution and then brine, dried (MgSO₄)and the solvent evaporated. The residue was purified by flashchromatography using methylene chloride/ethyl acetate (1/9) as eluent togive 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (6.2 g, 74%).

m.p. 171–173° C.

The starting material 4-hydroxy-6-methoxy-7-(2-methoxyethoxy)cinnolinewas obtained by adding a solution of sodium nitrite (3.9 g, 0.056 mol)in water (5 ml), dropwise, to a solution of2-amino-4-(2-methoxyethoxy)-5-methoxyacetophenone (12.18 g, 0.05 mol) inacetic acid (180 ml) and sulphuric acid (30 ml). After stirring for 90minutes at 80° C. the solution was concentrated to half its originalvolume and poured into ether (800 ml). The solid was collected byfiltration and suspended in water (400 ml). After adjusting to pH7.6with 2M aqueous sodium hydroxide solution the resulting solid wasfiltered off and washed with ether to give4-hydroxy-6-methoxy-7-(2-methoxyethoxy)cinnoline (8 g, 62%).

m.p. 232–234° C.

The starting material, 2-amino-4-(2-methoxyethoxy)-5-methoxyacetophenonewas obtained by adding iron powder (10 g, 0.18 mol), in portions, to asolution of 2-nitro-4-(2-methoxyethoxy)-5-methoxyacetophenone (17.3 g,0.064 mol) in acetic acid (80 ml) heated at 100° C. After stirring for30 minutes at 100° C., the mixture was cooled and water (20 ml) wasadded. The mixture was extracted with ethyl acetate, the combinedextracts were washed with water, saturated sodium carbonate solution andbrine and then dried (MgSO₄) and the solvent evaporated. The residue waspurified by flash chromatography using methylene chloride/ethyl acetate(8/2 followed by 75/25) as eluent to give2-amino-4-(2-methoxyethoxy)-5-methoxy-acetophenone (12.52 g, 81%).

m.p. 99–101° C.

The starting material,2-nitro-4-(2-methoxyethoxy)-5-methoxyacetophenone, was obtained byadding 3-methoxy-4-(2-methoxyethoxy)acetophenone (18.1 g, 0.08 mol) inportions over 50 minutes to a solution of 69.5% nitric acid (163 ml)cooled to 2° C. After stirring for 2 hours at ambient temperature, thereaction mixture was poured onto ice and extracted with ethyl acetate.The organic layer was washed with water and brine, dried (MgSO₄) and thesolvent evaporated. The residue was purified by flash chromatographyusing methylene chloride/ethyl acetate (95/5) as eluent to give2-nitro-4-(2-methoxyethoxy)-5-methoxyacetophenone (17.4 g, 80%) as apale yellow solid.

m.p. 120–124° C.

The starting material, 3-methoxy-4-(2-methoxyethoxy)acetophenone, wasobtained by heating a solution of 4-hydroxy-3-methoxyacetophenone (20 g,0.12 mol) and, bromomethyl methyl ether (12.4 ml, 0.13 mol) in DMF (400ml) containing potassium carbonate (49.8 g, 0.36 mol) at 50° C.overnight. After cooling, the reaction mixture was diluted with waterand adjusted to pH2. After extraction with ethyl acetate, the organiclayer was washed with brine, dried (MgSO₄) and evaporated. The residuewas purified by flash chromatography using petroleum ether/ethyl acetate(6/4 followed by 1/1) as eluent to give3-methoxy-4-(2-methoxyethoxy)acetophenone (21.8 g, 81%).

m.p. 84–86° C.

EXAMPLE 3

A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g,1.5 mmol), (prepared as described for the starting material in Example2), and 4-chloro-2-fluoroaniline (282 μl, 2.5 mmol) in DMF (5 ml) wastreated as described in Example 2, to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline asthe hydrochloride salt (450 mg, 72%).

m.p. 279–281° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.35(s, 3H); 3.8(t,2H); 4.05(s, 3H); 4.4(t, 2H); 7.4(s, 1H); 7.5(d, 1H); 7.7(t, 1H);7.75(d, 1H); 8.05(s, 1H); 8.3(s, 1H) MS-ESI: 378 [MH]⁺

Elemental analysis: Found C 52.1 H 4.5 N 10.2 C₁₈H₁₇N₃O₃ClF 1HClRequires C 52.2 H 4.4 N 10.1%

EXAMPLE 4

4-Chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.3 g, 1.1 mmol),(prepared as described for the starting material in Example 2), wasadded to a solution of 2,4-dihydroxytoluene (1 g, 8 mmol) and potassiumhydroxide (72 mg, 1.3 mmol) heated at 150° C. After stirring for 10minutes at 150° C., the mixture was allowed to cool and then partitionedbetween ethyl acetate and water. The pH was adjusted to 6 and theorganic layer was washed with water and brine and dried (MgSO₄) andevaporated. The solid was filtered off, washed with ether and driedunder vacuum to give a 1/1 mixture of4-(3-hydroxy-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline and4-(3-hydroxy-2-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline(150 mg, 38%).

¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.05 and 2.1(sx2, 3H); 3.35(s, 3H);3.8 (t, 2H); 4.1 and 4.15 (sx2, 3H); 4.45(t, 2H); 6,75(m, 1H); 6.85(m,1H); 7.25(d, 1H); 8.25(d, 1H); 7.7–7.8(m, 2H); 8.52 and 8.65(sx2, 1H)MS-ESI: 357 [MH]⁺379 [MNa]⁺

Elemental analysis: Found C 64.2 H 5.9 N 7.7 C₁₉H₂₀N₂O₅ Requires C 64.0H 5.7 N 7.9%

The starting material 2,4-dihydroxytoluene was prepared by adding borontribromide (3.1 ml, 3.2 mmol) to a solution of 2,4-dimethoxytoluene (1g, 6.5 mmol) in pentane (10 ml) at −70° C. The reaction mixture wasallowed to warm to ambient temperature and the mixture stirred for afurther 2 hours. Ice water and ethyl acetate were then added and theaqueous layer basified to pH9.5 with 2M aqueous sodium hydroxidesolution. After stirring for 10 minutes, the organic layer was separatedand the aqueous layer extracted with ethyl acetate. The combined organicextract was washed with brine, dried (MgSO₄) and the solvent removed byevaporation. The residue was purified by flash chromatography elutingwith methylene chloride/ethyl acetate (9/1) to give 2,4-dihydroxytoluene(759 mg, 94%) as a white solid.

EXAMPLE 5

A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g,0.74 mmol), (prepared as described for the starting material in Example2), and 4-bromo-2-fluoroaniline (155 mg, 0.82 mmol) in DMF (2.5 ml) washeated at 150° C. for 45 minutes. After cooling to ambient temperaturethe mixture was treated as described in Example 3 to give4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline asthe hydrochloride salt (150 mg, 44%).

m.p. 278–281° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.38(s, 3H); 3.85(t,2H); 4.1(s, 3H); 4.4(t, 2H); 7.45(s, 1H); 7.65(dd, 1H); 7.65(s, 1H);7.9(d, 1H); 8.1(s, 1H); 8.35(s, 1H) MS-ESI: 422 [MH]⁺

Elemental analysis: Found C 47.3 H 4.1 N 8.9 C₁₈H₁₇N₃O₃BrF 1HCl RequiresC 47.1 H 4.0 N 9.2%

EXAMPLE 6

A solution of 7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride (3.4g, 10 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline, (prepared asdescribed in EP 061741 A2), (1.84 g, 11 mmol) in DMF (42 ml) was heatedat 130° C. for 20 minutes. The resulting solid was filtered off, washedwith isopropanol, ether and dried under vacuum to give7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxycinnoline asthe hydrochloride salt (yellow solid. 3.5 g, 75%).

m.p. 280–284° C. ¹H NMR Spectrum: (DMSOd₆) 4.05(s, 3H); 5.4(s, 2H);7.2(d, 1H); 7.4–7.5(m, 3H); 7.5–7.55(m, 3H); 7.68(d, 1H); 8.2(s, 1H);8.35(s, 1H) MS-ESI: 426 [MH]⁺

Elemental analysis: Found C 57.4 H 4.2 N 9.5 C₂₂H₁₇N₃O₃ClF 1HCl RequiresC 57.2 H 3.9 N 9.1%

The starting material, 7-benzyloxy-4-chloro-6-methoxycinnolinehydrochloride, was obtained by heating a solution of7-benzyloxy-4-hydroxy-6-methoxycinnoline (11 g, 39 mmol) in thionylchloride (180 ml) containing DMF (1 ml) at reflux for 1 hour. Aftercooling, excess thionyl chloride was removed by evaporation andazeotroped with toluene. The residue was triturated with ether, filteredoff, washed with ether and dried under vacuum to give7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride as a cream solid(13.6 g, quantitative).

The starting material 7-benzyloxy-4-hydroxy-6-methoxycinnoline wasobtained by dropwise addition of a solution of sodium nitrite (4.9 g,0.072 mol) in water (10 ml) to a solution of2-amino-4-benzyloxy-5-methoxyacetophenone (16.3 g 0.06 mol) in aceticacid (250 ml) and 70% sulphuric acid (7.3 ml). After stirring for 30minutes, triethylamine (25 ml) was added and stirring was continued for6 hours. After adjusting to pH3.2 with 2M aqueous sodium hydroxidesolution, the solid was filtered off, washed with water, ether and driedunder vacuum to give 7-benzyloxy-4-hydroxy-6-methoxycinnoline (12.76 g,75%) as a brown solid.

m.p. 262–264° C.

The starting material 2-amino4-benzyloxy-5-methoxyacetophenone wasobtained by adding powdered iron (520 mg, 9.3 mmol) to a solution of2-nitro-4-benzyloxy-5-methoxyacetophenone (1 g, 3.3 mmol) in acetic acid(5 ml) heated at 100° C. After 30 minutes, the reaction mixture wascooled to ambient temperature and diluted with water. After extractionwith ethyl acetate the organic layer was washed with water, brine, dried(MgSO₄) and the solvent evaporated. The residue was purified by flashchromatography using petroleum ether/ethyl acetate (3/1) as eluent togive 2-amino-4-benzyloxy-5-methoxyacetophenone (629 mg, 70%) as a yellowsolid.

m.p. 139–141° C.

The starting material 2-nitro-4-benzyloxy-5-methoxyacetophenone wasobtained by, addition of a suspension of tin(IV)chloride (15.8 ml, 0.13mol) and 69.5% nitric acid (9.1 ml, 0.2 mol) in methylene chloride (110ml), dropwise over a period of 20 minutes, to a solution of4-benzyloxy-3-methoxyacetophenone (28.9 g, 0.11 mol) in methylenechloride (400 ml) cooled at −35° C.

After stirring for 20 minutes at −25° C., the mixture was warmed toambient temperature and poured onto ice/water (1 liter). Afterextraction with methylene chloride the organic layer was washed withbrine, dried (MgSO₄) and the solvent evaporated. The residue waspurified by flash chromatography using petroleum ether/ethyl acetate(7/3) as eluent to give 2-nitro-4-benzyloxy-5-methoxyacetophenone (27 g,76%) as a yellow solid.

m.p. 134–136° C.

The starting material, 4-benzyloxy-3-methoxyacetophenone, was obtainedby heating a solution of 4-hydroxy-3-methoxyacetophenone (20 g, 0.12mol), benzyl bromide (15.7 ml, 0.13 mol) and potassium carbonate (49.8g, 0.36 mol), in DMF (400 ml) at 40° C. overnight. After cooling, themixture was diluted with water, acidified to approximately pH3 andextracted with ethyl acetate. The organic layer was washed with brine,dried (MgSO₄) and the solvent evaporated. The residue was purified byflash chromatography using petroleum ether/ethyl acetate (8/2 followedby 65/35) as eluent to give 4-benzyloxy-3-methoxyacetophenone (30.3 g,99%).

m.p. 86–88° C.

EXAMPLE 7

Acetic anhydride (920 μl, 9.7 mmol) and 4-dimethylaminopyridine (80 mg,0.65 mmol) were added to a suspension of7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxycinnoline (3g, 6.5 mmol), (prepared as described in Example 6), in pyridine (50 ml).After heating at 110° C. for 25 minutes, the solid was filtered off,washed with water and ether and dried under vacuum. The solid wassuspended in 2M ethereal hydrogen chloride and the volatiles removed byevaporation to give4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxycinnoline asthe hydrochloride salt (yellow solid, 3.1 g, 94%).

m.p. 240–247° C. ¹H NMR Spectrum: (DMSOd₆) 2.35(s, 3H); 4.05(s, 3H);5.4(s, 2H); 7.35–7.5(m, 3H); 7.55(s, 1H); 7.55(d, 1H); 7.6(s, 1H);7.7(d, 1H); 7.95(d, 1H); 8.25(s, 1H); 8.4(s, 1H) MS-ESI: 468 [MH]⁺

Elemental analysis: Found C 56.8 H 4.2 N 8.2 C₂₄H₁₉N₃O₄ClF 1HCl RequiresC 57.2 H 4.0 N 8.3%

EXAMPLE 8

A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g,0.74 mmol), (prepared as described for the starting material in Example2), and 4-chloro-2-fluoro-5-hydroxyaniline (132 mg, 0.82 mmol),(prepared as described in EP 061741 A2), in DMF (2.5 ml) was heated at140° C. for 45 minutes. The work up procedure was as described inExample 6 and gave4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnolineas the hydrochloride salt (yellow solid, 157 mg, 49%).

m.p. 296–299° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.4(s, 3H); 3.85(t,2H); 4.1(s, 3H); 4.4(t, 2H); 7.2(d, 1H); 7.45(s, 1H); 7.65(d, 1H);8.05(s, 1H); 8.35(d, 1H) MS-ESI: 394 [MH]⁺

Elemental analysis: Found C 50.1 H 4.4 N 9.8 C₁₈H₁₇N₃O₄ClF 1HCl RequiresC 50.3 H 4.2 N 9.8%

EXAMPLE 9

A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.1 g,0.37 mmol), (prepared as described for the starting material in Example2), and 4-bromo-2-fluoro-5-hydroxyaniline (84 mg, 0.4 mmol), (preparedas described in EP 061741 A2), in DMF (2 ml) was heated at 140° C. for 1hour. The work up procedure was as described in Example 6 for theproduction of the final compound and gave in this example4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnolineas the hydrochloride salt (yellow solid, 127 mg, 72%).

m.p. 288–289° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 3.4(s, 3H); 3.85(t,2H); 4.1(s, 3H); 4.4(t, 2H); 7.2(d, 1H); 7.45(s, 1H); 7.75(d, 1H);8.1(s, 1H); 8.35(s, 1H) MS-ESI: 438 [MH]⁺

Elemental analysis: Found C 45.8 H 4.0 N 8.9 C₁₈H₁₇N₃O₄BrF 1HCl RequiresC 45.5 H 3.8 N 8.9%

EXAMPLE 10

A suspension of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnolinehydrochloride (0.17 g, 0.45 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline(102 mg, 0.63 mmol), (prepared as described in EP 061741 A2), in2-pentanol (3.5 ml) was heated at reflux overnight. After cooling,isopropanol was added. The solid formed was filtered off, washed withisopropanol, ether and dried under vacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(4-pyridylmethoxy)cinnolineas the hydrochloride salt (yellow solid, 194 mg, 86%).

m.p. 243–251° C. ¹H NMR Spectrum: (DMSOd₆) 4.12(s, 3H); 5.7(s, 2H);7.25(d, 1H); 7.55(s, 1H); 7.7(d, 1H); 7.9(d, 2H); 8.3(s, 1H); 8.4(s,1H); 8.9(d, 2H); 10.85(br s, 1H); 11.55(br s, 1H) MS-ESI: 427 [MH]⁺

Elemental analysis: Found C 49.6 H 3.9 N 10.8 C₂₁H₁₆N₄O₃ClF Requires C49.4 H 4.0 N 11.0% 1.3H₂O 1.65HCl

The starting material, 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnolinehydrochloride, was obtained by adding4-chloro-7-hydroxy-6-methoxycinnoline (200 mg, 0.95 mmol), followed by4-hydroxymethylpyridine (108 mg, 1 mmol) and1,1′-(azodicarbonyl)dipiperidine (647 mg, 2.5 mmol), in portions, to asolution of tri(n-butyl)phosphine (640 μg, 2.5 mmol) in methylenechloride (6 ml). After stirring for 1 hour at ambient temperature, asolution of 7M hydrogen chloride in isopropanol (300 μl, 2.1 mmol) wasadded. The resulting solid was filtered off, washed with methylenechloride and ether to give4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride as asolid (196 mg, 55%).

The starting material, 4-chloro-7-hydroxy-6-methoxycinnoline wasobtained by heating a solution of7-benzyloxy-4-chloro-6-methoxycinnoline hydrochloride (3.06 g, 9 mmol),(prepared as described for the starting material in Example 6), in TFA(30 ml) at reflux for 5 hours. After evaporation of the solvent, theresidue was suspended in water and adjusted to pH7 with saturatedaqueous sodium hydrogen carbonate solution. The resulting solid wasfiltered off, washed with water and ether and dried under vacuum to give4-chloro-7-hydroxy-6-methoxycinnoline as a yellow solid (1.78 g, 94%).

EXAMPLE 11

A suspension of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g,0.74 mmol), (prepared as described for the starting material in Example2), and 2-fluoro-5-hydroxy-4-methylaniline (126 mg 0.89 mmol) in2-pentanol (2.5 ml) was heated at reflux for 7.5 hours. After cooling,isopropanol was added and the solid was filtered off, washed withisopropanol and ether, and dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnolineas the hydrochloride salt (yellow solid 196 mg, 64%).

m.p. 283–290° C. ¹H NMR Spectrum: (DMSOd₆) 2.2(s, 3H); 3.4(s, 3H);3.8(t, 2H); 4.1(s, 3H); 4.35(t, 2H); 6.95(d, 1H); 7.25(d, 1H); 7.45(s,1H); 8.2(s, 1H); 8.22(s, 1H); 9.95(s, 1H); 11.2(br s, 1H) MS-ESI: 374[MH]⁺

Elemental analysis: Found C 55.5 H 5.5 N 10.0 C₁₉H₂₀N₃O₄F 0.1H₂O 1HClRequires C 55.4 H 5.2 N 10.2%

The starting material, 2-fluoro-5-hydroxy-4-methylaniline was obtainedas follows:

Methyl chloroformate (6.8 ml, 88 mmol) was added over 30 minutes to asolution of 4-fluoro-2-methylphenol (10 g, 79 mmol) in 6% aqueous sodiumhydroxide solution at 0° C. The mixture was stirred for 2 hours, thenextracted with ethyl acetate (100 ml). The ethyl acetate extract waswashed with water (100 ml) and dried (MgSO₄) and the solvent removed byevaporation to give 4-fluoro-2-methylphenyl methyl carbonate (11.4 g,78%) as an oil.

¹H NMR Spectrum: (DMSOd₆) 2.14(s, 3H), 3.81(s, 3H); 7.05(m, 1H);7.1–7.5(m, 2H)

A mixture of concentrated nitric acid (6 ml) and concentrated sulphuricacid (6 ml) was added slowly to a solution of 4-fluoro-2-methylphenylmethyl carbonate (11.34 g, 62 mmol) in concentrated sulphuric acid (6ml) such that the temperature of the reaction mixture was kept below 50°C. The mixture was stirred for 2 hours, then ice/water was added and theprecipitated product collected by filtration. The crude product waspurified by chromatography on silica eluting with methylenechloride/hexane progressing through increasingly polar mixtures tomethanol/methylene chloride (1/19) to give4-fluoro-2-methyl-5-nitrophenol (2.5 g, 22%) as a solid.

¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.31(s, 3H); 7.38(d, 1H); 7.58(d, 1H)MS: 171 [MH]⁺

A mixture of 4-fluoro-2-methyl-5-nitrophenol (2.1 g, 13 mmol), ironpowder (1 g, 18 mmol) and iron(II)sulphate (1.5 g, 10 mmol) in water (40ml) was heated at reflux for 4 hours. The reaction mixture was allowedto cool, neutralised with 2M aqueous sodium hydroxide solution andextracted with ethyl acetate (100 ml). The ethyl acetate extract wasdried (MgSO₄) and the solvent removed by evaporation to give2-fluoro-5-hydroxy-4-methylaniline (0.8 g, 47%) as a solid.

¹H NMR Spectrum: (DMSOd₆) 1.94(s, 3H); 4.67(s, 2H); 6.22(d, 1H); 6.65(d,1H); 8.68(s, 1H) MS: 142 [MH]⁺

EXAMPLE 12

A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnolinehydrochloride (83 mg, 0.2 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline(42 mg, 0.26 mmol), (prepared as described in EP 061741 A2), in2-pentanol (5 ml) containing DMF (0.5 ml) was heated at 120° C. for 2.5hours. The work up procedure was identical to the synthesis of the finalproduct in Example 11 and gave4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnolineas the hydrochloride salt (70 mg 65%).

m.p. 218–225° C. ¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.4(m, 2H); 3.35(m,6H); 3.9(m, 4H); 4.1(s, 3H); 4.4(t, 2H); 7.2(d, 1H); 7.45(s, 1H); 7.6(d,1H); 8.1(s, 1H); 8.35(s, 1H) MS-ESI: 463 [MH]⁺

Elemental analysis: Found C 46.1 H 5.2 N 9.5 C₂₂H₂₄N₄O₄ClF 2H₂O 1.9HClRequires C 46.5 H 5.3 N 9.9%

The starting material4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride wasobtained by adding 1-chloro-3-morpholinopropane (190 mg, 0.95 mmol),(prepared as described in U.S. Pat. No. 4,004,007), to a suspension of4-chloro-7-hydroxy-6-methoxycinnoline (0.2 g, 0.95 mmol), (prepared asdescribed for the starting material in Example 10), in DMF (5 ml)containing potassium carbonate (327 mg, 2.3 mmol) and potassium iodide(15 mg, 0.095 mmol). After heating at 80° C. for 2 hours, potassiumcarbonate (65 mg, 0.47 mmol) and more 1-chloro-3-morpholinopropane (95mg, 0.47 mmol) were added. After stirring for 4 hours at 80° C. thereaction mixture was cooled and 7M hydrogen chloride in isopropanol (407μl) was added. The solution was poured onto a Diaion (trade mark ofMitsubishi) HP20SS column, using water/methanol (100/0 to 0/100 as agradient) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline asan hydrochloride salt (175 mg, 44%).

EXAMPLE 13

A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnolinehydrochloride (0.1 g, 0.25 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline(57 mg, 0.35 mmol), (prepared as described in EP 061741 A2), in2-pentanol (5 ml) was heated at 120° C. for 2.5 hours. The solid wasfiltered off, washed with isopropanol and then ether and dried undervacuum to give4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnolineas the hydrochloride salt (yellow solid, 94 mg, 72%).

m.p. 240–245° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 1.9(m, 2H); 2.1(m,2H); 2.3(m, 2H); 3.1(m, 2H); 3.35(m, 2H); 3.65(m, 2H); 4.1(s, 3H);4.4(t, 2H); 7.2(d, 1H); 7.45(s, 1H); 7.65(d, 1H); 8.15(s, 1H); 8.35(s,1H) MS-ESI: 447 [MH]⁺

Elemental analysis: Found C 49.9 H 5.2 N 10.5 C₂₂H₂₄N₄O₃ClF Requires C50.1 H 5.2 N 10.6% 0.5H₂O 1.95HCl

The starting material,4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride wasobtained by adding 4-chloro-7-hydroxy-6-methoxycinnoline (0.3 g, 1.4mmol), (prepared as described for the starting material in Example 10),to a solution of 3-pyrrolidinopropyl chloride (275 mg, 1.5 mmol),(prepared as described in J. Amer. Chem. Soc. 1955, 77, 2272), in DMF (5ml) containing potassium carbonate (491 mg, 3.5 mmol) and potassiumiodide (24 mg, 0.14 mmol). After stirring at 80° C. for 3 hourspotassium carbonate (98 mg, 0.7 mmol) and 3-pyrrolidinopropyl chloride(137 mg, 0.7 mmol) were added. After 30 minutes, the mixture was cooledand 7M hydrogen chloride in isopropanol (407 μl) was added. The solutionwas poured onto a Diaion (trade mark of Mitsubishi) HP20SS TM columneluting with water/methanol (100/0 to 0/100 as a gradient). Afterevaporation of the solvent, the product was purified by preparative HPLCusing a reverse phase C18 column eluting with water/methanol (100/0 to80/20 as a gradient) to give after concentration,4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (265mg, 48%) as a yellow solid.

EXAMPLE 14

A suspension of 4-chloro-7-methoxycinnoline hydrochloride (196 mg, 0.85mmol) and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in 2-pentanol (5ml) was heated at reflux for 2 hours. After cooling, the solid wasfiltered off, washed with isopropanol, ether and dried under vacuum togive 4-(3-hydroxy-4methylanilino)-7-methoxycinnoline as thehydrochloride salt (yellow solid, 215 mg, 80%).

m.p. 270–275° C. ¹H NMR Spectrum: (DMSOd₆) 2.18(s, 3H); 4.0(s, 3H);6.88(d, 1H); 6.93(s, 1H); 7.25(d, 1H); 7.35(s, 1H); 7.52(dd, 1H); 8.4(s,1H); 8.75(d, 1H); 9.98(s, 1H); 11.65(br s, 1H) MS-ESI: 281 [MH]⁺

Elemental analysis: Found C 59.7 H 5.4 N 13.0 C₁₆H₁₅N₃O₂ 0.14H₂O 1HClRequires C 60.0 H 5.1 N 13.1%

The starting material 4-chloro-7-methoxycinnoline hydrochloride wasobtained by heating a solution of 4-hydroxy-7-methoxycinnoline (352 mg,2 mmol), (prepared as described in J. Chem. Soc. 1955, 2100), in thionylchloride (3.5 ml) containing DMF (20 μl) at reflux, for 1 hour. Afterremoving excess thionyl chloride by evaporation and azeotroping withtoluene. The residue was triturated with ether, filtered off and washedwith ether to give 4-chloro-7-methoxycinnoline hydrochloride as a yellowsolid (450 mg, 97%).

EXAMPLE 15

A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnolinehydrochloride (132 mg, 0.33 mmol), (prepared as described for thestarting material in Example 12), and 2-fluoro-5-hydroxy-4-methylaniline(56 mg, 0.39 mmol), (prepared as described for the starting material inExample 11), in 2-pentanol (2.5 ml) containing 7M hydrogen chloride inisopropanol (9drops) was heated at reflux for 30 minutes. After cooling,the solid was filtered off, washed with isopropanol, ether and driedunder vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnolineas an hydrochloride salt (yellow solid, 143 mg, 84%).

¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.2(s, 3H); 2.35(m, 2H); 3.3(m, 6H);3.9(br s, 4H); 4.0(s, 3H); 4.35(t, 2H); 6.95(d, 1H); 7.15(d, 1H);7.35(s, 1H); 8.1(s, 1H); 8.2(s, 1H) MS-ESI 443 [MH]⁺

Elemental analysis: Found C 53.0 H 6.0 N 10.2 C₂₃H₂₇N₄O₄F 0.5H₂O 2.8HClRequires C 53.6 H 6.0 N 10.6% 0.2 isopropanol

EXAMPLE 16

A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnolinehydrochloride (158 mg, 0.4 mmol), (prepared as described for thestarting material in Example 13), and 2-fluoro-5-hydroxy-4-methylaniline(67 mg, 0.48 mmol), (prepared as described for the starting material inExample 11), in 2-pentanol (5 ml) was heated at reflux for 1 hour. Aftercooling, the solid was filtered off, washed with isopropanol, ether anddried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-methoxy-7-(3-pyrrolidinopropoxy)cinnolineas the hydrochloride salt (yellow solid, 55 mg, 27%).

m.p. 247–253° C. ¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.05(m, 4H); 2.25(s,3H); 2.35(m, 2H); 3.25–3.5(br s, 6H); 4.05(s, 3H); 4.4(br s, 2H); 7.0(d,1H); 7.22(d, 1H); 7.45(s, 1H); 8.25(s, 1H) MS-ESI: 427 [MH]⁺

Elemental analysis: Found C 53.6 H 6.1 N 10.4 C₂₃H₂₇N₄O₃F 1H₂O 1.95HClRequires C 53.6 H 6.1 N 10.9%

EXAMPLE 17

A suspension of4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline (150 mg,0.46 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (78 mg, 0.56 mmol),(prepared as described for the starting material in Example 11), in2-pentanol (3 ml) and a 5M solution of hydrogen chloride in isopropanol(105 μl) was heated at reflux for 90 minutes. The solid obtained wasfiltered off, washed with isopropanol followed by ether to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnolinehydrochloride as a pale yellow solid (190 mg, 82%).

¹H NMR Spectrum: (DMSOd₆) 2.19(s, 3H); 2.69(s, 3H); 4.03(s, 3H); 5.39(s,2H); 6.98(d, 1H); 7.24(d, 1H); 7.66(s, 1H); 7.76(s, 1H); 8.16(d, 1H);8.27(s, 1H); 10.0(br s, 1H); 11.32(s, 1H) MS-ESI m/z: 427 [MH]⁺

Elemental analysis: Found C 50.7 H 4.4 N 11.0 C₂₁H₁₉N₄O₃SF 0.5H₂O1.65HCl Requires C 50.9 H 4.4 N 11.3%

The starting material4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline wasobtained by adding potassium carbonate (786 mg, 5.7 mmol) followed by4-chloromethyl-2-methylthiazole (308 mg, 2 mmol) to a suspension of4-chloro-7-hydroxy-6-methoxycinnoline (0.4 g, 1.9 mmol), (prepared asdescribed for the starting material in Example 10), in DMF (10 ml).After stirring for 4.5 hours at 60° C. the reaction mixture was dilutedwith water and acidified to pH4 with 2M hydrochloric acid. Afterextraction with ethyl acetate, the organic layer was washed with waterand then brine, dried (MgSO₄) and the solvent evaporated. The residuewas purified by flash chromatography using methylene chloride/ethylacetate (2/8) as eluent to give4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline as a solid(293 mg, 48%).

EXAMPLE 18

A suspension of 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline (109 mg, 0.35 mmol) and2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5 mmol), (prepared asdescribed for the starting material in Example 11), in 2-pentanol (3ml), DMF (0.5 ml) and a 5M solution of hydrogen chloride in isopropanol(74 μl, 0.35 mmol) was heated at reflux for 3 hours. The solution wasthen cooled to 0° C. and the resulting solid filtered off and washedwith ether to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnolinehydrochloride as a yellow solid (124 mg, 73%).

m.p. 215–221° C. ¹H NMR Spectrum: (DMSOd₆) 2.2(s, 3H); 3.9(s, 3H);4.05(s, 3H); 5.7(s, 2H); 6.99(d, 1H); 7.24(d, 1H); 7.67(s, 1H); 7.73(s,1H); 7.77(s, 1H); 8.20(d, 1H); 8.39(s, 1H); 9.96(s, 1H) 11.5(s, 11H)MS-ESI m/z: 410 [MH]⁺

Elemental analysis: Found C 51.3 H 4.9 N 13.7 C₂₁H₂₀N₅O₃F 0.9H₂O 1.8HClRequires C 51.3 H 4.8 N 14.3%

The starting material,4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]-cinnoline wasobtained by adding potassium carbonate (531 mg, 3.8 mmol) followed by2-chloromethyl-1-methylimidazole (232 mg, 1.4 mmol) to a suspension of4-chloro-7-hydroxy-6-methoxycinnoline (270 mg, 1.28 mmol), (prepared asdescribed for the starting material in Example 10), in DMF (6 ml). Afterstirring overnight at 40° C. the mixture was diluted with water andadjusted to pH7. After extraction with ethyl acetate the organic layerwas washed with water and then brine, dried (MgSO₄) and the solventevaporated. The residue was purified by flash chromatography usingmethylene chloride/methanol (98/2) as eluent to give4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline (111 mg,29%).

EXAMPLE 19

A solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnolinehydrochloride (268 mg, 0.71 mmol), (prepared as described for thestarting material in Example 10), and2-fluoro-5-hydroxy-4-methylaniline, (109 mg, 0.77 mmol), (prepared asdescribed for the starting material in Example 11), in 2-pentanol (6 ml)was heated at reflux for 4 hours. After dilution with isopropanol thesolid was filtered off, washed with isopropanol followed by ether togive4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)cinnolinehydrochloride (92 mg, 29%).

m.p. 244–252° C. ¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.2(s, 3H); 4.1(s,3H); 5.68(s, 2H); 7.0(s, 1H); 7.25(d, 1H); 7.5(s, 1H); 7.9(s, 2H);8.25(d, 2H); 8.85(s, 2H) MS-ESI m/z: 407 [MH]⁺

Elemental analysis: Found C 58.0 H 4.8 N 12.3 C₂₂H₁₉N₄O₃F 0.4H₂O 1.1HClRequires C 58.2 H 4.6 N 12.4%

EXAMPLE 20

A solution of4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnoline(242 mg 0.5 mmol) in a mixture of methanol (9 ml) and DMF (10.5 ml)containing 10% palladium-on-charcoal catalyst (100 mg) was stirred underhydrogen at 5 atmospheres pressure for 9 hours. The catalyst was removedby filtration and the solvent was evaporated. The residue was washedwith methanol and ether and dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnolineas a white solid (87 mg, 44%).

m.p. 267–273° C. ¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.18(s, 3H); 3.37(s,3H); 3.80(t, 2H); 4.04(s, 3H); 4.39(t, 2H); 6.8(d, 1H); 7.2(d, 1H);7.49(s, 1H); 7.79(s, 1H); 8.49(s, 1H) MS-ESI m/z: 375 [MH]⁺

Elemental analysis: Found C 58.9 H 5.3 N 7.5 C₁₉H₁₉N₂O₅F 0.7H₂O 0.06DMFRequires C 58.9 H 5.4 N 7.4%

The starting material,4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnolinewas obtained by heating a solution of5-benzyloxy-2-fluoro-4-methylphenol (314 mg, 1.3 mmol) and4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (280 mg, 1 mmol),(prepared as described for the starting material in Example 2), inpyridine (6 ml), at reflux for 15 hours. After evaporation of thesolvent, the residue was partitioned between ethyl acetate and wateradjusted to pH7. The organic layer was separated, washed with water andthen brine, dried (MgSO₄) and the solvent evaporated. The residue waspurified by flash chromatography using methylene chloride/ether (4/6followed by 3/7) as eluent to give4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-methoxy-7-(2-methoxyethoxy)cinnolineas a white solid (247 mg, 53%).

¹H NMR Spectrum: (DMSOd₆) 2.27(s, 3H); 3.37(s, 3H); 3.8(t, 2H); 4.0(s,3H); 4.4(t, 2H); 5.14(s, 2H); 7.26(d, 1H); 7.3–7.5(m, 6H); 7.5(s, 1H);7.81(s, 1H); 8.44(s, 1H)

The starting material 5-benzyloxy-2-fluoro-4-methylphenol, was obtainedby adding a solution of sodium nitrite (1.68 g, 24mmol) in water (3.5ml), dropwise, to a solution of 5-benzyloxy-2-fluoro-4-methylaniline(4.7 g, 20 mmol) in acetic acid (82 ml) and 70% sulphuric acid (3.15 ml)cooled at 10° C. The mixture was stirred vigorously for 20 minutes, thena solution of copper(II)nitrate trihydrate (481 g, 2 mol) in water (790ml) was added, followed by copper(II)oxide (3 g, 19 mmol). Afterstirring for 3 hours, the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then brine, dried (MgSO₄) andthe solvent evaporated. The resulting oil was purified by flashchromatography using petroleum ether/ether (85/15) as eluent to give5-benzyloxy-2-fluoro-4-methylphenol as an orange oil (1.25 g, 27%).

The starting material, 5-benzyloxy-2-fluoro-4-methylaniline, wasobtained by adding iron powder (2.88 g, 51 mmol), in portions, to asolution of 5-benzyloxy-2-fluoro-4-methylnitrobenzene (4.8 g, 18 mmol)in acetic acid (33 ml) and water (5.7 ml), at ambient temperature. Themixture was heated and after stirring at 100° C. for 10 minutes, it wascooled and partitioned between ethyl acetate and water. The organiclayer was washed with water, aqueous saturated sodium carbonate solutionand then brine, dried (MgSO₄) and the solvent evaporated. The residuewas purified by flash chromatography using petroleum ether/ethyl acetate(8/2) as eluent to give 5-benzyloxy-2-fluoro-4-methylaniline (3.65 g,87%).

The starting material 5-benzyloxy-2-fluoro-4-methylnitrobenzene wasobtained by adding benzyl bromide (3 ml, 25 mmol) to a solution of2-fluoro-5-hydroxy-4-methylnitrobenzene (3.92 mg, 23 mmol) in DMF (70ml) containing potassium carbonate (9.5 g, 68 mmol). After stirring for3 hours at 60° C. the mixture was diluted with water and adjusted topH2. After extraction with ethyl acetate, the organic layer was washedwith water and then brine, dried (MgSO₄) and the solvent evaporated. Thesolid was filtered off, washed with hexane and dried under vacuum togive 5-benzyloxy-2-fluoro-4-methylnitrobenzene (4.83 g, 80%).

The starting material 2-fluoro-5-hydroxy-4-methylnitrobenzene, wasobtained by adding 2M aqueous sodium hydroxide solution (13.1 ml),dropwise, to a solution of2-fluoro-5-methoxycarbonyloxy-4-methylnitrobenzene (6 g, 26 mmol),(prepared as described in European Patent Publication No. 307777), inmethanol (70 ml) cooled at 0° C. After stirring for 30 minutes, themixture was concentrated by evaporation. After dilution with water, thesolution was adjusted to pH2 and extracted with ethyl acetate. Theorganic layer was washed with water and then brine, dried (MgSO₄) andthe solvent evaporated to give 2-fluoro-5-hydroxy-4-methylnitrobenzeneas a yellow solid (4 g, 90%).

EXAMPLE 21

A solution of 4-chloro-6,7-dimethoxycinnoline hydrochloride (261 mg, 1mmol), (prepared as described for the starting material in Example 1),and 2-fluoro-5-hydroxy-4-methylaniline (170 mg, 1.2 mmol), (prepared asdescribed for the starting material in Example 11), in 2-pentanol (5 ml)was heated at 120° C. for 3 hours. After cooling, the solid was filteredoff, washed with isopropanol and ether and dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6,7-dimethoxycinnoline as anhydrochloride salt (301 mg, 82%).

m.p. 251–253° C. ¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 2.22(s, 3H); 4.05(s,3H); 4.07(s, 3H); 6.97(d, 1H); 7.24(d, 1H); 7.39(s, 1H); 8.08(s, 1H);8.22(d, 1H) MS-ESI m/z: 330 [MH]⁺

Elemental analysis: Found C 55.2 H 4.8 N 11.1 C₁₇H₁₆N₃O₃F 0.1H₂O 1HClRequires C 55.6 H 4.7 N 11.4%

EXAMPLE 22

A solution of 4-chloro-6,7-dimethoxycinnoline hydrochloride (261 mg, 1mmol), (prepared as described for the starting material in Example 1),and 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (prepared asdescribed in EP 061741), was treated in a manner similar to thatdescribed in Example 21 in order to produce4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxycinnoline as anhydrochloride salt (315 mg, 82%).

m.p. 255–256° C. ¹H NMR Spectrum: (DMSOd₆; CF₃COOD) 4.05(s, 3H); 4.07(s,3H); 7.19(d, 1H); 7.4(s, 1H); 7.65(d, 1H); 8.07(s, 1H); 8.34(d, 1H)MS-ESI m/z: 350 [MH]⁺

Elemental analysis: Found C 49.5 H 3.8 N 10.5 C₁₆H₁₃N₃O₃ClF 1HClRequires C 49.8 H 3.7 N 10.9%

EXAMPLE 23

A solution of 4-chloro-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnoline(130 mg, 0.41 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5mmol), (prepared as described for the starting material in Example 11),in 2-pentanol (3 ml) containing 5M hydrogen chloride in isopropanol (2drops) was heated at reflux for 45 minutes. After cooling the solid wasfiltered off, washed with isopropanol followed by ether to give4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnolineas an hydrochloride salt (159 mg, 88%).

m.p. 250–256° C. ¹H NMR Spectrum: (DMSOd₆) 2.21(s, 3H); 3.27(s, 3H);3.51(dd, 2H); 3.66(dd, 2H); 3.90(t, 2H); 4.06(s, 3H); 4.37(t, 2H);6.98(d, 1H); 7.25(d 1H); 7.46(s, 1H); 8.18(d, 1H); 8.23(s, 1H); 9.94(s,1H); 11.2(s, 1H) MS-ESI m/z: 418 [MH]⁺

Elemental analysis: Found C 55.2 H 5.7 N 8.8 C₂₁H₂₄N₃O₅F 0.2H₂O 1HClRequires C 55.1 H 5.6 N 9.2%

The starting compound4-chloro-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-cinnoline was obtainedby adding triphenylphosphine (995 mg, 3.8 mmol), followed bydiethyleneglycol (271 μl, 2.2 mmol) and diethyl azodicarboxylate (598μl, 3.8 mmol), dropwise, to a suspension of4-chloro-7-hydroxy-6-methoxycinnoline (0.4 g, 1.9 mmol), (prepared asdescribed for the starting material in Example 10), in methylenechloride (12 ml) under nitrogen and cooled to 10° C. After stirring for1 hour, the solvent was evaporated and the residue purified by flashchromatography using methylene chloride/ethyl acetate (5/5 followed by4/6) as eluent to give4-chloro-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnoline (366 mg, 91%).

EXAMPLE 24

A solution of 4,6-dichlorocinnoline (200 mg, 1 mmol) and2-fluoro-5-hydroxy-4-methylaniline (169 mg, 1.2 mmol), (prepared asdescribed for the starting material in Example 11), in 2-pentanol (4 ml)containing 7M isopropanolic hydrogen chloride (2 drops) was heated atreflux for 45 minutes. After cooling the solid was filtered off, washedwith isopropanol followed by ether to give6-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)cinnoline hydrochloride(326 mg, 95%).

¹H NMR Spectrum: (DMSOd₆) 2.20(s, 3H); 6.98(d, 1H); 7.26(d, 1H); 8.18(s,2H); 8.35(s, 1H); 9.1(s, 1H); 9.98(br s, 1H) MS-ESI: 304 [MH]⁺

Elemental Analysis: Found C 53.4 H 4.0 N 11.9 C₁₅H₁₁N₃OFCl 0.95HCl0.1H₂O Requires C 53.0 H 3.6 N 12.4%

The starting material was prepared as follows:

A solution of 4-hydroxy-6-chlorocinnnoline (1 g, 5.5 mmol), (J. Chem.Soc. 1961, 1828), in thionyl chloride (10 ml) and DMF (0.1 ml) washeated at reflux for 20 minutes. Toluene was added and the volatileswere removed by evaporation. The solid was partitioned between ethylacetate and water and the aqueous layer adjusted to pH7 with sodiumhydrogen carbonate. The organic layer was washed with water and brine,dried (MgSO₄) and the volatiles removed by evaporation. The residue waspurified by column chromatography eluting with methylene chloride/ether(95/5) to give 4.6-dichlorocinnoline (804 mg, 73%).

m.p. 111–113° C. ¹H NMR Spectrum: (CDCl₃) 7.85(dd, 1H); 8.18(d, 1H);8.52(d, 1H); 9.36(s, 1H) MS-EI: 199 [M·]⁺

Elemental Analysis: Found C 48.5 H 2.1 N 14.0 C₈H₄N₂Cl₂ Requires C 48.3H 2.0 N 14.1%

EXAMPLE 25

A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnolinehydrochloride (150 mg, 0.36 mmol), (prepared as described for thestarting material in Example 12), 4-chloro-2-fluoroaniline (77 mg, 0.53mmol) in 2-pentanol (4 ml) and 5M isopropanolic hydrogen chloride (1 ml)was heated at 120° C. for 1 hour. The mixture was allowed to cool andisopropanol was added. The resulting precipitate was collected byfiltration, washed with ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnolinehydrochloride (185 mg, 98%).

¹H NMR Spectrum: (DMSOd₆) 2.3–2.4(m, 2H); 3.1–3.2(m, 2H); 3.3–3.4(m,2H); 3.5–3.6(m, 2H); 3.8–3.95(m, 2H); 3.95–4.1(m, 2H); 4.08(s, 3H);4.38(t, 2H); 7.55(dd, 1H), 7.57(s, 1H); 7.71(t, 1H); 7.80(dd, 1H);8.31(d, 1H); 8.4(s, 1H) MS-ESI: 447 [MH]⁺

Elemental Analysis: Found C 50.0 H 5.2 N 10.2 C₂₂H₂₄N₄O₂FCl Requires C50.1 H 5.1 N 10.6% 1.95HCl 0.5H₂O

EXAMPLE 26

A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnolinehydrochloride (130 mg, 0.32 mmol), (prepared as described for thestarting material in Example 13), and 4-chloro-2-fluoroaniline (70 mg,0.48 mmol), in 2-pentanol (4 ml) and 5M isopropanolic hydrogen chloride(1 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off,washed with isopropanol and then ether and dried under vacuum to give4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnolinehydrochloride (110 mg, 66%).

¹H NMR Spectrum: (DMSOd₆; CD₃COOD) 1.9–2.1(m, 4H); 2.25–2.35(m, 2H);3.0–3.3(br m, 2H); 3.36(t, 2H); 3.4–3.7(m, 2H); 4.06(s, 3H); 4.38(t,2H); 7.46(s, 1H); 7.55(d, 1H); 7.72(t, 1H); 7.75(dd, 1H); 8.21(s, 1H);8.33(s, 1H) MS-ESI: 431 [MH]⁺

Elemental Analysis: Found C 51.2 H 5.4 N 10.3 C₂₂H₂₄N₄O₂FCl 1.9HCl1.1H₂O Requires C 50.8 H 5.4 N 10.8%

EXAMPLE 27

A solution of 4-chloro-7-(2-methoxyethoxy)cinnoline (156 mg, 0.65 mmol)and 2-fluoro-5-hydroxy-4-methylaniline (111 mg, 0.78 mmol), (prepared asdescribed for the starting material in Example 11), in 2-pentanol (8 ml)and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for2.5 hours. The solid was filtered off, washed with isopropanol and thenether and dried under vacuum to give4-(2-fluoro-5-hydroxy-4-methylanilino)-7-(2-methoxyethoxy)cinnolinehydrochloride (207 mg, 84%).

¹H NMR Spectrum: (DMSOd₆) 2.19(s, 3H); 3.4(s, 3H); 3.8(t, 2H); 4.4(t,2H); 6.96(d, 1H); 7.25(d, 1H); 7.38(s, 1H); 7.61(d, 1H); 8.21(s, 1H);8.71(d, 1H); 9.94(s, 1H) MS-ESI: 344 [MH]⁺

Elemental Analysis: Found C 57.1 H 5.4 N 11.3 C₁₈H₁₈N₃O₃F 0.15H₂O0.95HCl Requires C 56.8 H 5.1 N 11.0%

The starting material was prepared as follows:

Diethyl azodicarboxylate (349 μl, 2.2 mmol) was added dropwise to asuspension of 4-chloro-7-hydroxycinnnoline (200 mg, 1.1 mmol),triphenylphosphine (580 mg, 2.2 mmol) and 2-methoxyethanol (105 μl, 1.3mmol) in methylene chloride (6 ml) cooled at 10° C. The mixture wasstirred for 30 minutes and further triphenylphosphine (145 mg),2-methoxyethanol (20 μl) and diethyl azodicarboxylate (88 μl) wereadded. The mixture was then allowed to warm to ambient temperature andstirred for 30 minutes. The volatiles were removed by evaporation andthe residue was purified by column chromatography eluting with ethylacetate/petroleum ether (7/3) and followed by column chromatographyeluting with cyclohexane/ethyl acetate 35/65 to give4-chloro-7-(2-methoxyethoxy)cinnoline (158 mg, 60%).

¹H NMR Spectrum: (CDCl₃) 3.5(s, 3H); 3.88(m, 2H); 4.36(m, 2H); 7.58(dd,1H); 7.77(d, 1H); 8.08(d, 1H); 9.2(s, 1H)

Aluminium trichloride (2.6 g, 19 mmol) was added in portions to asuspension of 4-chloro-7-methoxycinnoline (0.9 g, 3.8 mmol), (J. Chem.Soc. 1955, 2100), in benzene (15 ml) and the mixture was heated atreflux for 1 hour. The solvent was removed by evaporation and theresidue was partitioned between ice/water and ethyl acetate. Aqueoussaturated sodium chloride solution was added and the organic layer wasseparated. The organic layer was washed with brine, dried (MgSO₄) andthe solvent removed by evaporation. The residue was triturated withether, collected, filtered and dried under vacuum to give4-chloro-7-hydroxycinnoline (368 mg, 53%).

¹H NMR Spectrum: (DMSOd₆) 7.6(dd, 1H); 7.66(d, 1H); 8.11(d, 1H); 9.35(s,1H)

EXAMPLE 28

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium  12.0 Maize starch paste (5% w/v paste)  2.25Magnesium stearate  3.0 (b) Tablet II mg/tablet Compound X  50 LactosePh.Eur 223.75 Croscarmellose sodium  6.0 Maize starch  15.0Polyvinylpyrrolidone (5% w/v paste)  2.25 Magnesium stearate  3.0 (c)Tablet III mg/tablet Compound X  1.0 Lactose Ph.Eur  93.25Croscarmellose sodium  4.0 Maize starch paste (5% w/v paste)  0.75Magnesium stearate  1.0 (d) Capsule mg/capsule Compound X  10 LactosePh.Eur 488.5 Magnesium stearate  1.5 (e) Injection I (50 mg/ml) CompoundX  5.0% w/v 1N Sodium hydroxide solution  15.0% v/v 0.1N Hydrochloricacid (to adjust pH to 7.6) Polyethylene glycol 400  4.5% w/v Water forinjection to 100% (f) Injection II (10 mg/ml) Compound X  1.0% w/vSodium phosphate BP  3.6% w/v 0.1N Sodium hydroxide solution  15.0% v/vWater for injection to 100% (g) Injection III (1 mg/ml.buffered to pH6)Compound X  0.1% w/v Sodium phosphate BP  2.26% w/v Citric acid  0.38%w/v Polyethylene glycol 400  3.5% w/v Water for injection to 100% NoteThe above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)–(c) may be entericcoated by conventional means. for example to provide a coating ofcellulose acetate phthalate.

1. A method for producing an antiangiogenic and/or vascular permeabilityreducing effect in a warm-blooded animal in need of such treatment whichcomprises administering to said animal a vascular endothelial growthfactor inhibiting effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof:

wherein: Z represents —O—, —NH—, —S— or —CH₂—; m is an integer from 1 to5; R¹ represents hydrogen, hydroxy, halogeno, nitro, cyano,trifluoromethyl, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkylthio or NR⁶R⁷, whereinR⁶ and R⁷, which may be the same or different, each represents hydrogenor C₁₋₃alkyl; R² represents hydrogen, hydroxy, fluoro, chloro, methoxy,amino or nitro; R³ represents hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino or nitro; R⁴ is a groupR⁵—X¹, wherein: X¹ represents —O—; and R⁵ is selected from one of thefollowing five groups: 1) C₁₋₅alkyl; 2) C₂₋₄alkylX^(3a)R^(14a) (whereinX^(3a) represents —O— and R^(14a) represents C₁₋₃alkyl); 3)C₂₋₃alkylX^(4a)C₂₋₃alkylX^(5a)R^(15a) (wherein X^(4a) and X^(5a) areeach —O— and R^(15a) represents hydrogen or C₁₋₃alkyl); 4)C₁₋₅alkylR^(25a) (wherein R^(25a) is a 5 or 6 membered saturatedheterocyclic group with one or two heteroatoms, selected independentlyfrom O, S and N, which heterocyclic group is linked to C₁₋₅alkyl througha carbon atom and which heterocyclic group may bear one or twosubstituents selected from halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl andC₁₋₄alkoxy) or C₂₋₅alkylR^(26a) (wherein R^(26a) is a 5 or 6 memberedsaturated heterocyclic group with one or two heteroatoms of which one isN and the other is selected independently from O, S and N, whichheterocyclic group is linked to C₂₋₅alkyl through a nitrogen atom andwhich heterocyclic group may bear one or two substituents selected fromhalogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); wherein the 5 or6 membered heterocyclic ring is selected from pyrrolidinyl, piperazinyl,piperidinyl, 1,3-dioxolan-2-yl, 1,3-dioxan-2-yl, 1,3-dithiolan-2-yl,1,3-dithian-2-yl, morpholino and thiomorpholino; and 5)(CH₂)_(na)R^(20a) (wherein na is an integer from 0 to 4 and R^(20a) is aphenyl group or a 5 or 6 membered aromatic heterocyclic group with 1 to3 heteroatoms selected from O, N and S, which phenyl or aromaticheterocyclic group may carry up to 5 substituents selected fromhalogeno, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄hydroxyalkoxy,carboxy, cyano, CONR^(21a)R^(22a) and NR^(23a)COR^(24a) (whereinR^(21a), R^(22a), R^(23a) and R^(24a), which may be the same ordifferent, each represents hydrogen or C₁₋₄alkyl); wherein the 5 or 6membered aromatic heterocyclic group is selected from pyridyl,imidazolyl, thiazolyl, thienyl, pyridazinyl and triazolyl.
 2. The methodas claimed in claim 1 wherein R² is hydrogen.
 3. The method as claimedin claim 1 wherein Z is —NH—.
 4. The method as claimed in claim 1wherein R¹ is methoxy.
 5. The method as claimed in claim 1 wherein thephenyl group bearing (R³)_(m) is a 2-fluoro-5-hydroxy-4-methylphenyl,4-chloro-2-fluoro-5-hydroxyphenyl, 4-chloro-3-hydroxyphenyl,4-bromo-3-hydroxyphenyl, 3-hydroxy-4-methylphenyl, or a4-bromo-2-fluoro-5-hydroxyphenyl group.
 6. The method as claimed inclaim 1 wherein R⁵ is selected from one of the following four groups: 1)C₂₋₄alkylX^(3a)R^(14a) (wherein X^(3a) represents —O— and R^(14a)represents C₁₋₃alkyl); 2) C₂₋₃alkylX^(4a)C₂₋₃alkylX^(5a)R^(15a) (whereinX^(4a) and X^(5a) are each —O— and R^(15a) represents hydrogen orC₁₋₃alkyl); 3) C₁₋₄alkylR^(25a) (wherein R^(25a) is selected frompyrrolidinyl, piperazinyl, piperidyl, 1,3-dioxolan-2-yl,1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, such thatR^(25a) is linked to C₁₋₄alkyl through a carbon atom) orC₂₋₄alkylR^(26a) (wherein R^(26a) is selected from morpholino,pyrrolidin-1-yl, piperazin-1-yl and piperidino); and 4)(CH₂)_(na)R^(20a) (wherein na is an integer from 1 to 3 and R^(20a) is a5 or 6 membered aromatic heterocyclic group with 1 to 2 heteroatomsselected from O, N and S, which aromatic heterocyclic group may besubstituted as hereinbefore defined, wherein the 5 or 6 memberedaromatic heterocyclic group is selected from pyridyl, imidazolyl,thiazolyl, thienyl, pyridazinyl and triazolyl.
 7. The method as claimedin claim 1 wherein R⁵ is selected from one of the following fourgroups: 1) C₂₋₃alkylX^(3a)R^(14a) (wherein X^(3a) represents —O— andR^(14a) represents C₁₋₂alkyl); 2) C₂₋₃alkylX^(4a)C₂₋₃alkylX^(5a)R^(15a)(wherein X^(4a) and X^(5a) are each —O— and R^(15a) represents hydrogenor C₁₋₂alkyl); 3) C₁₋₂alkylR^(25a) (wherein R^(25a) is selected frompyrrolidinyl, piperazinyl, piperidyl, 1,3-dioxolan-2-yl,1,3-dioxan-2-yl, 1,3-dithiolan-2-yl and 1,3-dithian-2-yl, such thatR^(25a) is linked to C₁₋₂alkyl through a carbon atom) orC₂₋₃alkylR^(26a) (wherein R^(26a) is selected from morpholino,piperidino, piperazin-1-yl and pyrrolidin-1-yl); and 4)(CH₂)_(na)R^(20a) (wherein na is an integer from 1 to 3 and R^(20a) isselected from pyridyl, imidazolyl, thiazolyl, thienyl and pyridazinyl,and R^(20a) may be substituted with one substituent selected fromhalogeno, C₁₋₂alkyl, C₁₋₂alkoxy, C₁₋₂hydroxyalkyl, C₁₋₂hydroxyalkoxy,carboxy, cyano, CONR^(21a)R^(22a) and NR^(23a)COR^(24a) (whereinR^(21a), R^(22a), R^(23a) and R^(24a), which may be the same ordifferent, each represents hydrogen or C₁₋₂alkyl).
 8. The method asclaimed in claim 1 wherein R⁴ is a group R⁵—X¹, wherein: X¹ is —O—; andR⁵ is 2-methoxyethyl, 3-methoxypropyl, 2-morpholinoethyl,3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl,2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl,2-(pyrrolidin-1-yl)ethyl, 3-(pyrrolidin-1-yl)propyl,2-(1,3-dioxolan-2-yl)methyl, 3-(1,3-dioxolan-2-yl)ethyl,2-(2-methoxyethylamino)ethyl, 2-methylthiazol-4-ylmethyl,1-methylimidazol-2-ylmethyl, 4-pyridylmethyl, 2-(4-pyridyl)ethyl or3-(4-pyridyl)propyl.
 9. A method for producing an antiangiogenic and/orvascular permeability reducing effect in a warm-blooded animal in needof such treatment which comprises administering to said animal avascular endothelial growth factor inhibiting effective amount of acompound of formula Ib, or a pharmaceutically acceptable salt thereof:

wherein R^(1b) is hydrogen, C₁₋₃alkoxy, or halogeno; R^(2b) is hydrogen;X^(1b) is —O—; R^(4b) is C₁ ₋₃alkyl, 2-(C₁₋₃alkoxy)ethyl, benzyl,4-pyridyl(C₁₋₃alkyl), morpholino(C₁₋₃alkyl), pyrrolidino(C₁₋₃alkyl),2-methylthiazol-4-yl(C₁₋₃alkyl), 1-methylimidazol-2-yl(C₁₋₃alkyl) and2-((C₁₋₃alkoxy)(C₁₋₃alkoxy))ethyl; Z^(b) is —NH— or —O—; mb is 2 or 3;and the phenyl group bearing (R^(3b))_(mb) is selected from:3-hydroxy-4-methylphenyl, 4-chloro-2-fluorophenyl,4-bromo-2-fluorophenyl, 4-chloro-2-fluoro-5-hydroxyphenyl,5-acetoxy-4-chloro-2-fluorophenyl, 2-fluoro-5-hydroxy-4-methylphenyl and4-bromo-2-fluoro-5-hydroxyphenyl.
 10. The method as claimed in claim 1wherein the compound of formula I is selected from:4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,4-(4-bromo-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline,4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morphohnopropoxy)cinnoline,4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline,4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline,or a pharmaceutically acceptable salt thereof.